Compound capable of binding s1p receptor and pharmaceutical use thereof

ABSTRACT

A compound having an ability to bind to an S1P receptor and represented by formula (I), a salt thereof, a solvate thereof or a prodrug thereof is useful for prevention and/or treatment of rejection of transplantation, graft-versus-host disease, autoimmune disease, allergic disease and the like: 
     
       
         
         
             
             
         
       
     
     wherein ring A is a cyclic group; ring B is a cyclic group which may have substituent(s); X is a spacer having 1 to 8 atoms in its main chain, etc.; Y is a spacer having 1 to 10 atoms in its main chain, etc.; n is 0 or 1, wherein when n is 0, m is 1 and R 1  is a hydrogen atom or a substituent, and wherein when n is 1, m is 0 or an integer of 1 to 7 and R 1  is a substituent, and wherein m is 2 or more, R 1 s are the same or different.

CROSS REFERENCE TO RELATED APPLICATIONS

This is a Continuation application of U.S. application Ser. No.12/879,158 filed Sep. 10, 2010 (allowed), which is a Continuationapplication of U.S. application Ser. No. 10/569,831, now U.S. Pat. No.7,825,109, filed Feb. 28, 2006, which is a National Stage Application ofPCT/JP2004/012768 filed Aug. 27, 2004, which claims benefit of JapanesePatent Application No. 2003-306088 filed Aug. 29, 2003, JapaneseApplication No. 2004-110573 filed Apr. 2, 2004, Japanese Application No.2004-169958 filed Jun. 8, 2004, and Japanese Application No. 2004-198523filed Jul. 5, 2004. The entire disclosures of the above-notedapplications are incorporated herein by reference.

TECHNICAL FIELD

The present invention relates to a compound having an ability to bind toa sphingosine-1-phosphate (hereinafter referred to as S1P in some cases)receptor which is useful as a medicament and a medicament containing thesame as an active ingredient.

More specifically, the present invention relates to:

(1) a compound having an ability to bind to an S1P receptor (inparticular, EDG-6, preferably EDG-1 and EDG-6);(2) a medicament containing the compound as an active ingredient;(3) a compound represented by the following formula (I):

wherein all symbols have the same meanings as described below;

a prodrug thereof and a salt thereof; and

(4) a medicament containing the compound represented by formula (I), aprodrug thereof and a salt thereof as an active ingredient.

BACKGROUND ART

Sphingosine-1-phosphate (S1P) having the structural formula representedby formula (A) is a lipid that is produced by the intracellularmetabolic turnover of sphingolipids or the extracellular action ofsecretory sphingosine kinase. It is pointed out that S1P acts as anintercellular and intracellular messenger (Biochem. Pharm., 58, 201(1999)).

As receptors of S1P, EDG-1 which is a G protein-coupled receptor and itsanalogous molecules, EDG-3, EDG-5, EDG-6 and EDG-8 (also called S1P₁,S1P₃, S1P₂, S1P₄ and S1P₅, respectively) are known. They are called EDGreceptor family together with EDG-2, EDG-4 and EDG-7 which are receptorsof lysophosphatidic acid (LPA). S1P receptors binds to S1P and deliversignals into cells via G-protein coupled with the receptors. Gs, Gi, Gqand G_(12/13) are known as, G-proteins to which S1P receptor can couple,and it is considered that the receptor relates to responses such asincrease of cell proliferation, suppression of cell proliferation,induction of cell chemotaxis and inhibition of cell chemotaxis.

As biological action of S1P, inhibition of migration of smooth musclecells or cancer cells, platelet aggregation, induction of cellchemotaxis, inhibition of cell chemotaxis and the like are known invitro experiments, and as the results of in vivo experiments, it isknown that S1P shows effects of controlling blood pressure, promotingangiogenesis, reducing renal blood flow, inhibiting lung fibrosis,promoting the lymphocyte homing into lymphatic organs and the like. Itis considered that these various physiological effects are mediated byS1P receptors existing in cell membrane. However, it has been scarcelyclarified excluding some cases which subtypes of S1P receptors mediatethese effects in practice.

Recently, from the study for EDG-1 knock-out mice, it is stronglyindicated that S1P induced angiogenesis via EDG-1 (Yujing Liu, et al.,J. Clin. Invest., 106, 951 (2000)). Therefore, it is suggested thatEDG-1 agonist is used as a treating agent for disease caused byanangioplasia. For example, it is used as an agent for prevention and/ortreatment of peripheral arterial disease such as arteriosclerosisobliterans, thromboangiitis obliterans, Buerger's disease or diabeticneuropathy; varicose vein such as hemorrhoid, anal fissure, analfistula; dissecting aneurysm of the aorta, sepsis, inflammatory diseasesuch as angiitis, nephritis or pneumonia, various edematous diseasecaused by ischemia of various organ or increase of the bloodpermeability, for example, myocardial infarction, cerebral infarction,angina, DIC (disseminated intravascular coagulation), pleuritis,congestive heart failure or multiple organ failure. Furthermore, it isused as an accentuation agent for healing of wound in cornea, skin,digestive organs or the like, for example, an agent for preventionand/or treatment for bedsore, burn, chronic ulcerative colitis orCrohn's disease. In addition, it is used as a preoperative,postoperative and/or prognostic activator for blood vessel accompanyingtransplantation of various organs, for example, as an adhesion activatorof transplanted organs such as heart transplantation, renaltransplantation, dermal transplantation or liver transplantation.

Different from other EDG receptors, on the other hand, EDG-6 islocalized and strongly expressed in cells of the lymphatic andhematopoietic systems including spleen, leukocytes, lymph gland, thymus,bone marrow, lung and the like, which suggests the possibility ofclosely relating to the effects of S1P in the course of inflammation orin the immune system (Biochem. Biophys. Res. Commun., 268, 583 (2000)).

Moreover, it is known that the EDG-6 polypeptide or its homolog isconcerned with immunomodulation, antiinflammation and the like, whichbrings about the potential usability of these substances in treatingautoimmune diseases (systemic lupus erythematosus, rheumatoid arthritis,myasthenia gravis and the like), allergic diseases (atopic dermatitis,asthma and the like), inflammation, infection, ulcer, lymphoma,malignant tumor, leukemia, arteriosclerosis, diseases associated withlymphocyte infiltration into a tissue and the like.

Accordingly, it appears that drugs acting against EDG-6 are useful aspreventives and/or remedies for rejection in transplantation, rejectionof a transplanted organ, transplantation versus host disease, autoimmunediseases (systemic lupus erythematosus, rheumatoid arthritis, myastheniagravis and the like), allergic diseases (atopic dermatitis, asthma andthe like), inflammation, infection, ulcer, lymphoma, malignant tumor,leukemia, arteriosclerosis, diseases associated with lymphocyteinfiltration into a tissue and the like.

It is known that 2-amino-2-[2-(4-octylphenyl)ethyl]-1,3-propanediolhydrochloride (CAS Registration No. 162359-56-0, hereinafter referred toas “FTY720”) having a sphingosine-like structure has an immunesuppressive effect. However, the target molecule thereof has remainedunknown for a long time. Recently, it is clarified that FTY720 isphosphorylated in vivo and the phosphorylated FTY-720 binds to an S1Preceptor (see Science, 296, 346 (2002); and J. Biol. Chem., 277, 21453(2002)). As the results of detailed studies, it is found out thatphosphorylated FTY720 binds to multiple subtypes of the SP receptors,i.e., EDG-1, EDG-3, EDG-6 and EDG-8.

FTY720 is one of 2-amino-1,3-propanediol compounds represented byformula (Y):

wherein R^(Y) represents a linear or branched carbon chain which mayhave a substituent(s), aryl which may have a substituent(s), cycloalkylwhich may have a substituent(s), etc; and R^(2Y), R^(3Y), R^(4Y) andR^(5Y) are the same or different and each represents a hydrogen atom,alkyl, aralkyl, acyl or alkoxycarbonyl (only necessary parts of thedefinitions of the symbols are extracted). It is disclosed that thesecompounds are useful as immunosuppressants (see WO 94/008943).

As the results of a recent clinical trial on FTY720 in human kidneytransplantation, it is reported that FTY720 has an effect ofsignificantly lowering the incidence rate of acute rejection. It isfound out that FTY720 exerts the major effect of reducing the lymphocytecount in the peripheral blood without suppressing the proliferation oractivation, the memory function and the ability to recognize a foreignmatter in viral infection of lymphocytes. Thus, it is indicated thatFTY720 is useful in treating diseases such as rejection intransplantation.

However, it is also reported that FTY720 has a side effect of causingbradycardia after administration (J. Am. Soc. Nephrol., 13, 1073(2002)). Therefore, attention should be sufficiently given in using it.Accordingly, there has been required a highly safe drug which shows ahigh therapeutic effect and yet has little side effect.

Recently, it is reported that an EDG-1 agonist is useful as animmunosuppressant. However, it has never been stated that an EDG-6agonist or antagonist is useful as an immunosuppressant (see WO03/061567).

Moreover, it is disclosed that a compound represented by formula (S):

wherein Ar^(S) represents phenyl or naphthyl; A^(S) represents carboxy,etc.; n^(S) represents 2, 3 or 4; R^(1S) and R^(2S) each independentlyrepresents a hydrogen atom, a halogen atom, hydroxy, carboxy, C1-6 alkylwhich may be substituted with 1 to 3 halogen atoms or phenyl which maybe substituted with 1 to 3 halogen atoms; R^(3S) represents a hydrogenatom or C1-4 alkyl which may be substituted with 1 to 3 hydroxy orhalogen atoms; R^(4S)s each independently represents hydroxy, a halogenatom, carboxy, etc.; C^(S) represents C1-8 alkyl, C1-8 alkoxy, phenyl,etc. or C^(S) is nil; and B^(S) represents phenyl, C5-16 alkyl, etc.(only necessary parts of the definitions of the symbols are extracted);

a pharmaceutically acceptable salt thereof and a hydrate thereof, and

a compound represented by formula (T):

wherein Ar^(T) represents phenyl or naphthyl; A^(T) represents carboxy,etc.; m^(T) represents 0 or 1; n^(T) represents 0 or 1; R^(1T) andR^(2T) each independently represents a hydrogen atom, a halogen atom,hydroxy, carboxy, C1-4 alkyl or phenyl which may be substituted with ahalogen atom, etc.; R^(3T) represents a hydrogen atom, C1-4 alkyl whichmay be substituted with hydroxy or a halogen atom, etc.; R^(4T)'s eachindependently represents a halogen atom, C1-4 alkyl, C1-3 alkoxy, etc.;C^(T) represents C1-8 alkyl, C1-8 alkoxy, phenyl, etc. or C^(T) is nil;and B^(T) represents phenyl, C5-16 alkyl, etc. (only necessary parts ofthe definitions of the symbols are extracted);

a pharmaceutically acceptable salt thereof and a hydrate thereof areuseful as EDG-1 agonists (see WO 03/062248 and WO 03/062252).

Also, as an EDG-1 agonist, known is a carboxylic acid derivativerepresented by formula (Z):

wherein R^(1Z) represents C1-8 alkyl, C1-8 alkoxy, a halogen atom, nitroor trifluoromethyl; ring A^(Z) represents a C5-7 monocyclic carbocyclicgroup or a 5- to 7-membered monocyclic heterocyclic group containing oneor two nitrogen atoms, one oxygen atom and/or one sulfur atom; E^(Z)represents —CH₂—, —O—, —S— or —NR^(6Z)—, in which R^(6Z) represents ahydrogen atom or C1-8 alkyl; R^(2Z) represents C1-8 alkyl, C1-8 alkoxy,a halogen atom, nitro or trifluoromethyl; R^(3Z) represents a hydrogenatom or C1-8 alkyl; R^(6Z) represents a hydrogen atom or C1-8 alkyl, orR^(2Z) and R^(4Z) may be taken together to form —CH₂CH₂— or —CH═CH—;G^(Z) represents —CONR^(7Z)—, —NR^(7Z)CO—, —SO₂NR^(7Z)—, —NR^(7Z)SO₂—,—CH₂NR^(7Z)— or —NR^(7Z)CH₂—, in which R^(7Z) represents a hydrogenatom, C1-8 alkyl or the like; Q^(Z) represents C1-4 alkylene or thelike; p^(Z) represents 0 or an integer of 1 to 5; q^(Z) represents aninteger of 4 to 6; r^(Z) represents 0 or an integer of 1 to 4;

represents a single bond or a double bond, a prodrug thereof or anon-toxic salt thereof (WO02/092068).

DISCLOSURE OF THE PRESENT INVENTION

Immunosuppressants are useful in preventing and/treating inflammatorydiseases, allergic diseases and/or rejection in transplantation.However, it is known that many of immunosuppressants used at presenthave severe side effects at a considerably high frequency. Furthermore,they suffer from reduction in the effects thereof within a short periodof time. It is feared that FTY720 as described above is also affected bya metabolic enzyme. Moreover, it is reported that FTY720 actually showsside effects including bradycardia at clinical trials. Therefore, it hasbeen urgently required to develop a drug which exhibits a prolongedpharmacological effect, has little side effects, shows a high safety andis never affected by metabolic enzymes.

As the results of intensive studies on sphingosine-1-phosphate (S1P)receptors being useful as medicines, the present inventors unexpectedlyfound out that the present invention compounds have a strong ability tobind to EDG-6. They also found out that some of the present inventioncompounds have a strong agonistic activity against EDG-1. They havefurther found out that these invention compounds having an ability tobind to EDG-6, in particular, the present invention compounds having theagonistic activity against EDG-1 have additional effects of reducinglymphocytes in the peripheral blood and immunosuppressive action.Furthermore, they have surprisingly found out that the pharmacologicalactivities of these invention compounds can be sustained over a longtime, thereby completing the present invention.

The present invention relates to the followings:

1. A compound represented by formula (I):

wherein ring A represents a cyclic group;

ring B represents a cyclic group which may further have asubstituent(s);

X represents a bond or a spacer having 1 to 8 atoms in its main chain inwhich one atom in the spacer may be taken together with a substituent onring B to form a ring group which may have a substituent(s);

Y represents a bond or a spacer having 1 to 10 atoms in its main chainin which one atom in the spacer may be taken together with a substituenton ring B to form a ring group which may have a substituent(s);

n represents 0 or 1, wherein when n is 0, m is 1 and R¹ represents ahydrogen atom or a substituent, and when n is 1, m is 0 or an integer of1 to 7 and R¹ represents a substituent in which when m is 2 or more,plural R¹s are the same or different,

a salt thereof, a solvate thereof or a prodrug thereof.

2. The compound according to the above item 1, which is a compoundrepresented by formula (I):

wherein all symbols have the same meanings as in the above item 1, and

wherein a compound represented by formula (Ia) is excluded:

wherein R^(1a) represents C1-8 alkyl, C1-8 alkoxy, a halogen atom, nitroor trifluoromethyl;

ring A^(a) represents a C5-7 monocyclic carbocyclic group or a 5- to7-membered monocyclic heterocyclic group containing one or two nitrogenatoms, one oxygen atom and/or one sulfur atom;

E^(a) represents —CH₂—, —O—, —S— or —NR^(6a)—, in which R^(6a)represents a hydrogen atom or C1-8 alkyl;

R^(2a) represents C1-8 alkyl, C1-8 alkoxy, a halogen atom, nitro ortrifluoromethyl;

R^(3a) represents a hydrogen atom or C1-8 alkyl;

R^(4a) represents a hydrogen atom or C1-8 alkyl, or

R^(2a) and R^(4a) may be taken together to form —CH₂CH₂— or —CH═CH—;

G^(a) represents —CONR^(7a)—, —NR^(7a)CO—, —SO₂NR^(7a)—, —NR^(7a)SO₂—,—CH₂NR^(7a)— or —NR^(7a)CH₂—, in which R^(7a) represents a hydrogenatom, C1-8 alkyl, Cyc1 or C1-8 alkyl substituted with Cyc1, and Cyc1represents a C5-7 monocyclic carbocyclic group or a 5- to 7-memberedmonocyclic heterocyclic group containing one or two nitrogen atoms, oneoxygen atom and/or one sulfur atom;

Q^(a) represents C1-4 alkylene or

wherein J¹, J², J³ and J⁴ each independently represents a carbon atom ora nitrogen atom in which the number of the nitrogen atom(s) is 2 orless; R^(5a) represents (1) C1-8 alkyl, (2) a halogen atom, (3) nitro,(4) cyano, (5) trifluoromethyl, (6) trifluoromethoxy, (7) phenyl, (8)tetrazolyl, (9) —OR^(9a), (10) —SR^(10a), (11) —COOR^(11a), (12)—NR^(12a)R^(13a), (13) —CONR^(14a)R^(15a), (14) —SO₂NR^(16a)R^(17a),(15) —NR^(18a)COR^(19a), (16) —NR^(20a)SO₂R^(21a), (17) —SO₂R^(22a), or(18) —OP(O)(OR^(23a))₂, in which R^(9a) to R^(18a), R^(20a) and R^(23a)each independently represents a hydrogen atom, C1-8 alkyl, Cyc2 or C1-8alkyl substituted with Cyc2, or R^(12a) and R^(13a), R^(14a) andR^(15a), or R^(16a) and R^(17a) may be taken together with a nitrogenatom to which they are bound, to form a 5- to 7-membered monocyclicheterocyclic group containing one or two nitrogen atoms, one oxygen atomand/or one sulfur atom, in which the heterocyclic group may besubstituted with C1-8 alkyl, hydroxy or amino; R^(19a) and R^(21a) eachindependently represents C1-8 alkyl, Cyc2 or C1-8 alkyl substituted withCyc2; R^(22a) represents hydroxy, C1-8 alkyl, Cyc2 or C1-8 alkylsubstituted with Cyc2; and Cyc2 represents a C5-7 monocyclic carbocyclicgroup or a 5- to 7-membered monocyclic heterocyclic group containing oneor two nitrogen atoms, one oxygen atom and/or one sulfur atom;

p represents 0 or an integer of 1 to 5;

q represents an integer of 4 to 6;

r represents 0 or an integer of 1 to 4;

s represents 0 or an integer of 1 to 4; and

represents a single bond or a double bond.

3. The compound according to the above item 2, which is represented byformula (IA):

wherein Y¹ and Y² each independently represents a bond or a spacerhaving 1 to 9 atoms in its main chain in which the total atom number ofthe main chains of Y¹ and Y² is 9 or less;

R⁷ represents a hydrogen atom or a substituent, or may be taken togetherwith one atom in the spacer represented by Y¹ and/or Y² to form anitrogen-containing heterocyclic group which may have a substituent(s);and

other symbols have the same meanings as described in the above item 1.

4. The compound according to the above item 2, which is represented byformula (IB):

wherein ring B¹ represents a nitrogen-containing heterocyclic groupwhich may have a substituent(s) in which a nitrogen atom in the spacerrepresented by Y is taken together with a substituent on ring B and Y¹;and

other symbols have the same meanings as described in the above items 1and 3.

5. The compound according to the above item 2, wherein ring A is abenzene, indane, indene or naphthalene ring.6. The compound according to the above item 2, wherein ring B is a C5-12monocyclic or bicyclic carbocyclic group which may have asubstituent(s).7. The compound according to the above item 6, wherein ring B is abenzene or naphthalene ring which may have a substituent(s).8. The compound according to the above item 2, wherein ring B is a 5- to12-membered monocyclic or bicyclic heterocyclic group which contains 1to 3 hetero atoms selected from an oxygen atom, a nitrogen atom and asulfur atom and may be partially or fully saturated.9. The compound according to the above item 2, wherein ring B is adihydronaphthalene, indene, 6,7-dihydro-5H-benzo[7]annulene, pyridine,indole, chromene, benzofuran, benzothiophene, benzoxazole,dihydrobenzoxepine, tetrahydroisoquinoline, isoindoline ortetrahydrobenzazepine ring which may have a substituent (s).10. The compound according to the above item 4, wherein thenitrogen-containing heterocyclic group represented by ring B¹ is apyrrole, tetrahydropyridine, dihydropyrrole or tetrahydroazepine ring.11. The compound according to the above item 2, wherein X is a divalentgroup having 1 to 8 atoms in its main chain which is 1 to 4 combinationsselected from the group consisting of C1-8 alkylene which may besubstituted, C2-8 alkenylene which may be substituted, a nitrogen atomwhich may be substituted, —CO—, —O—, C3-6 cycloalkylene which may besubstituted and phenylene which may be substituted.12. The compound according to the above item 11, wherein X is —CH₂—,—(CH₂)₂—, —(CH₂)₃—, —(CH₂)₄—, —(CH₂)₅—, —(CH₂)₆—, —(CH₂)₇—, —(CH₂)₈—,—CH₂—O—, —(CH₂)₂—O—, —(CH₂)₃—O—, —(CH₂)₄—O—, —(CH₂)₅—O—, —CH═CH—CH₂—O—or -cyclopropylene-CH₂—O—, which each may be substituted, in which theright side of each group is bound to ring B.13. The compound according to the above item 2, wherein Y is a divalentgroup having 1 to 10 atoms in its main chain which is 1 to 4combinations selected from the group consisting of C1-10 alkylene whichmay be substituted, C2-10 alkenylene which may be substituted, C2-10alkynylene which may be substituted, a nitrogen atom which may besubstituted, —CO—, —O—, —S—, phenylene which may be substituted,-(aziridine which may be substituted)-, -(azetidine which may besubstituted)-, -(pyrrolidine which may be substituted)-, -(piperidinewhich may be substituted)-, -(piperazine which may be substituted)- and-(tetrahydropyridine which may be substituted)-.14. The compound according to the above item 13, wherein Y is—(CH₂)₃—NHCH₂—, —(CH₂)₃—NCH₃—CH₂—, —(CH₂)₃—NH—(CH₂)₂—,—(CH₂)₂—NH—(CH₂)₂—, —(CH₂)₂—CONHCH₂—, —(CH₂)₂—CONH-(m-phenylene)-,—CR^(Y1)═CH—CH₂—NH—(CH₂)₄—, —CR^(Y1)═CH—CH₂—NH—(CH₂)₅—,—CR^(Y1)═CH—CH₂—NH—(CH₂)₂—, —CH═CR^(Y1)—CH₂—NH—(CH₂)₂—,—CR^(Y1)═CH—CH₂—NH—CH₂—, —CH₂-(azetidine)-, —(CH₂)₂-(azetidine)-,—(CH₂)₃-(azetidine)-, —CR^(Y1)═CH—CH₂-(azetidine)-,—CH═CR^(Y1)—CH₂-(azetidine)-, —(CH₂)₃-(piperidine)- or—CR^(Y1)═CH—CH₂-(piperidine)-, which each may be substituted, in whichR^(Y1) represents a hydrogen atom, a halogen atom or C1-4 alkyl whichmay be substituted with 1 to 3 halogen atoms, and the right side of eachgroup is bound to ring B.15. The compound according to the above item 3, wherein Y¹ is a divalentgroup having 1 to 4 atoms in its main chain which is 1 to 4 combinationsselected from the group consisting of C1-3 alkylene and —CO—.16. The compound according to the above item 15, wherein Y¹ is —CH₂—,—(CH₂)₂—, —(CH₂)₂—CO—, —CO—(CH₂)₂— or —(CH₂)₃—, which each may besubstituted.17. The compound according to the above item 3, wherein Y² is a divalentgroup having 1 to 5 atoms in its main chain which is 1 to 4 combinationsselected from the group consisting of C1-3 alkylene which may besubstituted and phenylene which may be substituted.18. The compound according to the above item 17, wherein Y² is —CH₂—,—(CH₂)₂— or -(m-phenylene)-, which each may be substituted.19. The compound according to the above item 2, wherein the substituentrepresented by R¹ is a halogen atom, C1-20 alkyl which may besubstituted, or C1-20 alkyloxy which may be substituted.20. The compound according to the above item 19, wherein the substituentrepresented by R¹ is fluoro, chloro, bromo, methyl, trifluoromethyl ormethoxy.21. The compound according to the above item 3, wherein R⁷ is a hydrogenatom or C1-20 alkyl which may be substituted.22. The compound according to the above item 2, which is a compoundrepresented by formula (I-S-3a):

wherein X^(S) has the same meaning as X described in the above item 1,in which X^(S) is not —(CH₂)_(q)-E^(a)-; R^(S0), R^(S1), R^(S2), R^(S3),R^(S4), R^(S5), R^(S6), R^(S7), R^(S8), R^(S9), R^(S10) and R^(S11) eachindependently represents a hydrogen atom, a halogen atom, or C1-4 alkylwhich may be substituted with 1 to 3 halogen atoms; E^(a), q and othersymbols have the same meanings as described in the above items 1 and 2,or

formula (I-S-7a):

wherein R^(S0), R^(S1), R^(S2), R^(S3), R^(S4), R^(S5) and R^(S6) eachhas the same meaning as described above; R^(S12), R^(S13), R^(S14) andR^(S15) each independently represents a hydrogen atom, a halogen atom,or C1-4 alkyl which may be substituted with 1 to 3 halogen atoms; E^(a),q and other symbols have the same meanings as described in the aboveitems 1 and 2.

23. The compound according to the above item 2, which is a compoundrepresented by formula (I-T):

wherein R^(S16), R^(S17), R^(S18), R^(S19) and R^(S20) eachindependently represents a hydrogen atom, a halogen atom, or C1-4 alkylwhich may be substituted with 1 to 3 halogen atoms; and other symbolshave the same meanings as described in the above items 1, 2 and 22.

24. The compound according to the above item 2, which is a compoundrepresented by formula (I-U):

wherein R^(S21), R^(S22), R^(S23), R^(S24), R^(S25) and R^(S26) eachindependently represents a hydrogen atom, a halogen atom, or C1-4 alkylwhich may be substituted with 1 to 3 halogen atoms; and other symbolshave the same meanings as described in the above items 1, 2 and 22.

25. The compound according to the above item 2, which is

-   (1) N-{(2E)-3-[4-(3-phenylpropoxy)phenyl]prop-2-enyl}-β-alanine,-   (2) N-{[6-(3-phenylpropoxy)-2-naphthyl]methyl}-β-alanine,-   (3) 1-{[6-(3-phenylpropoxy)-2-naphthyl]methyl}azetidine-3-carboxylic    acid,-   (4)    1-{[6-(3-phenylpropoxy)-2-naphthyl]methyl}piperidine-4-carboxylic    acid,-   (5)    N-{(2E)-3-[2-methyl-4-(3-phenylpropoxy)phenyl]prop-2-enyl}-β-alanine,-   (6)    1-{(2E)-3-[4-(3-phenylpropoxy)phenyl]-2-propenyl}piperidine-4-carboxylic    acid,-   (7)    1-{(2E)-3-[4-(3-phenylpropoxy)phenyl]-2-propenyl}azetidine-3-carboxylic    acid,-   (8) N-{3-[4-(3-phenylpropoxy)phenyl]propyl}-β-alanine,-   (9) 3-({(2E)-3-[4-(3-phenylpropyl)phenyl]-2-butenyl}amino)propanoic    acid,-   (10)    3-({(2E)-3-[4-(3-cyclohexylpropoxy)-2-methylphenyl]-2-propenyl}amino)propanoic    acid,-   (11)    1-{[1-methyl-6-(4-phenylbutoxy)-3,4-dihydro-2-naphthalenyl]methyl}-3-azetidinecarboxylic    acid,-   (12) N-{[1-(5-phenylpentyl)-1H-indol-5-yl]methyl}-β-alanine,-   (13)    3-[4-[4-(3-phenylpropoxy)phenyl]-3,6-dihydropyridin-1(2H)-yl]propanoic    acid,-   (14)    1-(6-[3-(4-chlorophenyl)propoxy]-1-methyl-3,4-dihydro-2-naphthalenylmethyl)-3-azetidinecarboxylic    acid, or-   (15)    1-(6-[3-(4-fluorophenyl)propoxy]-1-methyl-3,4-dihydro-2-naphthalenylmethyl)-3-azetidinecarboxylic    acid.    26. The compound according to the above item 1, which is-   (1)    N-((2E)-3-{2-methyl-4-[(5-phenylpentyl)oxy]phenyl}prop-2-enyl)-β-alanine,-   (2) N-((2E)-3-{4-[(5-phenylpentyl)oxy]phenyl}-2-propenyl)-β-alanine,    or-   (3)    3-({[1-methyl-6-(4-phenylbutoxy)-3,4-dihydro-2-naphthalenyl]methyl}amino)propanoic    acid.    27. A pharmaceutical composition which comprises a compound    represented by formula (I) in the above item 1, a salt thereof, a    solvate thereof or a prodrug thereof.    28. The pharmaceutical composition according to the above item 27,    which is an S1P receptor binding agent.    29. The pharmaceutical composition according to the above item 28,    which is an EDG-6 binding agent which may have an ability to bind to    EDG-1.    30. The pharmaceutical composition according to the above item 29,    wherein the EDG-6 binding agent which may have an ability to bind to    EDG-1 is an EDG-6 agonist which may have an agonistic activity    against EDG-1.    31. The pharmaceutical composition according to the above 27, which    is an agent for preventing and/or treating a disease related to    EDG-1 and/or EDG-6.    32. The pharmaceutical composition according to the above 31,    wherein the disease related to EDG-1 and/or EDG-6 is rejection in    transplantation, autoimmune disease and/or allergic disease.    33. The pharmaceutical composition according to the above 31,    wherein the disease related to EDG-1 and/or EDG-6 is rejection in    transplantation of kidney, liver, heart, lung, dermal graft, cornea,    bone, bone marrow cells and/or pancreatic islet cells, collagen    disease, systemic lupus erythematosus, rheumatoid arthritis,    multiple sclerosis, psoriasis, inflammatory bowel disease, Crohn's    disease, autoimmune diabetes, lung fibrosis, atopic dermatitis    and/or asthma.    34. The pharmaceutical composition according to the above item 27,    which is an immunosuppressant agent.    35. The pharmaceutical composition according to the above item 27,    which is an agent causing lymphopenia.    36. The pharmaceutical composition according to any one of the above    28, 31, 34 and 35, which comprises-   (1) 2-[3-(4-(5-phenylpentyloxy)phenyl)propanoylamino]acetic acid,-   (2) 3-[3-(4-(5-phenylpentyloxy)phenyl)propylamino]propanoic acid,-   (3) 3-[2-(4-(5-phenylpentyloxy)phenyl)ethylamino]propanoic acid,-   (4) 2-[3-(4-(5-phenylpentyloxy)phenyl)propylamino]acetic acid,-   (5) 2-[N-methyl-3-(4-(5-phenylpentyloxy)phenyl)propylamino]acetic    acid,-   (6)    N-((2E)-3-{2-methyl-4-[(5-phenylpentyl)oxy]phenyl}prop-2-enyl)-β-alanine,-   (7) N-((2E)-3-{4-[(5-phenylpentyl)oxy]phenyl}-2-propenyl)-β-alanine,-   (8)    3-({[1-methyl-6-(4-phenylbutoxy)-3,4-dihydro-2-naphthalenyl]methyl}amino)propanoic    acid,-   (9)    3-carboxyl-5-[3-(4-(5-phenylpentyloxy)phenyl)propanoylamino]benzoic    acid, or-   (10)    2-chloro-5-[3-(2-fluoro-4-(5-phenylpentyloxy)phenyl)propanoylamino]benzoic    acid,

a salt thereof, a solvate thereof or a prodrug thereof.

37. A medicament comprising the compound represented by formula (I)according to the above item 1, a salt thereof, a solvate thereof or aprodrug thereof in combination with one or at least two selected fromthe group consisting of an antimetabolite, an alkylating agent, a T cellactivation inhibitor, a calcineurin inhibitor, a proliferation signalinhibitor, a steroid, an immunosuppressant agent, an antibody used inimmune suppression, an agent for treating rejection, an antibiotic, anantiviral agent and an antifungal agent.38. An immunosuppressant agent and/or an agent causing lymphopenia,which comprises a compound which has an ability to bind to EDG-6 and mayhave an ability to bind to EDG-1.39. The immunosuppressant agent and/or the agent causing lymphopeniaaccording to the above 38, which is an agent for preventing and/ortreating rejection in transplantation, autoimmune disease and/orallergic disease.40. A method for preventing and/or treating a disease related to EDG-1and/or EDG-6 in a mammal, which comprises administering to a mammal aneffective amount of the compound represented by formula (I) according tothe above item 1, a salt thereof, a solvate thereof or a prodrugthereof.41. A method for immune suppression and/or lymphopenia in a mammal,which comprises administering to a mammal an effective amount of thecompound represented by formula (I) according to the above item 1, asalt thereof, a solvate thereof or a prodrug thereof.42. Use of the compound represented by formula (I) according to theabove item 1, a salt thereof, a solvate thereof or a prodrug thereof forthe manufacture of a medicament for preventing and/or treating a diseaserelated to EDG-1 and/or EDG-6.43. Use of the compound represented by formula (I) according to theabove item 1, a salt thereof, a solvate thereof or a prodrug thereof forthe manufacture of an immunosuppressant agent and/or an agent causinglymphopenia.44. A medicament comprising a compound having an ability to bind to S1Preceptor.45. The medicament according to the above item 44, which is animmunosuppressant agent and/or an agent causing lymphopenia.46. The medicament according to the above item 45, wherein the S1Preceptor is EDG-1 and EDG-6.47. The medicament according to the above item 45, wherein the S1Preceptor is EDG-6.48. The medicament according to the above item 46, wherein the compoundhaving an ability to bind to EDG-1 and EDG-6 is an EDG-1 agonist and anEDG-6 agonist.49. The medicament according to the above item 47, wherein the compoundhaving an ability to bind to EDG-6 is an EDG-6 agonist.50. The medicament according to the above item 45, which is an agent forpreventing and/or suppressing rejection.51. The medicament according to the above item 50, wherein the rejectionis rejection of transplantation, T-cell mediated rejection, acuterejection and/or chronic rejection.52. The medicament according to the above item 51, wherein thetransplantation is transplantation of organ, tissue and/or cells.53. The medicament according to the above item 52, wherein the organ iskidney, liver, heart, and/or lung, the tissue is dermal graft, cornea,and/or bone, and the cells are bone marrow cells and/or pancreatic isletcells.54. The medicament according to the above item 45, which is an agent forpreventing and/or treating autoimmune disease and/or allergic disease.55. The medicament according to the above item 54, wherein the allergicdisease is atopic dermatitis.56. The medicament according to the above item 45, wherein the agentcausing lymphopenia is an agent for promoting the lymphocytes hominginto a secondary lymphatic tissue, an agent for suppressing therecirculation of lymphocytes from lymph nods into the blood, or an agentfor protecting lymphocytes in the peripheral blood during cancertherapy.57. A medicament comprising a compound having an ability to bind to S1Preceptor in combination with one or at least two selected from the groupconsisting of an antimetabolite, an alkylating agent, a T cellactivation inhibitor, a calcineurin inhibitor, a proliferation signalinhibitor, a steroid, an immunosuppressant agent, an antibody used inimmune suppression, an agent for treating rejection, an antibiotic, anantiviral agent and an antifungal agent.58. A production process of the compound represented by formula (I), asalt thereof, a solvate thereof or a prodrug thereof, and the like.

In the present specification, S1P means sphingosine-1-phosphate((2S,3R,4E)-2-amino-3-hydroxyoctadec-4-enyl-1-phosphate). EDG meansendothelial differentiation gene which is a generic term including fromEDG-1 to EDG-8. Among these EDGs, EDG-1, EDG-3, EDG-5, EDG-6 and EDG-8(separately named S1P₁, S1P₃, S1P₂, S1P₄ and S1P₅, respectively) areregarded as S1P receptors.

In the present specification, the “compound having an ability to bind toreceptor” includes agonists, antagonists and inverse agonists.

In the present specification, the agonist includes full agonists andpartial agonists.

In the present specification, the disease related to EDG-6 includes, forexample, rejection in transplantation, rejection of a transplantedorgan, transplantation versus host disease, autoimmune diseases(systemic lupus erythematosus, rheumatoid arthritis, myasthenia gravisand the like), allergic diseases (atopic dermatitis, asthma and thelike), inflammation, infection, ulcer, lymphoma, malignant tumor,leukemia, arteriosclerosis, diseases associated with lymphocyteinfiltration into a tissue and the like.

In the present specification, the disease related to EDG-1 includes, forexample, acute heart failure, angina, stroke, traumatic injury, geneticdiseases, peripheral arterial disease such as arteriosclerosisobliterans, thromboangiitis obliterans, Buerger's disease, or diabeticneuropathy, sepsis, angiitis, nephritis, pneumonia, cerebral infarction,myocardial infarction, edematous diseases, varicose vein such ashemorrhoid, anal fissure, anal fistula, dissecting aneurysm of theaorta, DIC, pleuritis, congestive heart failure, multiple organ failure,bedsore, burn, chronic ulcerative colitis, Crohn's disease,osteoporosis, lung fibrosis, interstitial pneumonia, chronic hepatitis,cirrhosis hepatis, chronic renal failure, glomerulosclerosis and thelike. EDG-1 also participates in preoperative, postoperative and/orprognostic activation for blood vessel accompanying transplantation ofvarious organs, for example, an adhesion activation of transplantedorgans such as heart transplantation, renal transplantation, dermaltransplantation or liver transplantation.

In the present specification, the rejection in transplantation means anacute rejection occurring within 3 months after transplanting a graft,chronic rejection occurring thereafter and transplantation versus hostdisease.

In the present specification, the graft means a transplanted organ (forexample, kidney, liver, heart, lung, small intestine, etc.), atransplanted tissue (for example, a dermal graft (for example, afull-thickness skin graft, an epidermal graft, a dermis graft, a Davisgraft, etc.), cornea, bone, a fetal tissue, etc.) or transplanted cells(for example, bone marrow cells, hematopoietic stem cells, peripheralblood stem cells, cord blood stem cells, pancreatic islet cells,Langerhans cells being part thereof, hepatocytes, neuronal cells,intestinal epithelial cells; etc.). As preferable organs, kidney, liver,heart and lung may be cited. As preferable tissues, a dermal graft andcornea may be cited. As preferable cells, bone marrow cells andpancreatic islet cells may be cited.

In the present specification, the T cell-mediated means that T cellsparticipate in some step in the formation, exacerbation or continuationof a disease.

In the present specification, the autoimmune disease includes, forexample, collagen disease, systemic lupus erythematosus, rheumatoidarthritis, multiple sclerosis, nephrotic syndrome, lupus nephritis,Sjoegren's syndrome, scleroderma, multiple myositis, psoriasis,inflammatory bowel disease, Crohn's disease, mixed connective tissuedisease, primary myxedema, Addison's disease, hypolastic anemia,autoimmune hemolytic anemia, autoimmune thrombopenia, autoimmunediabetes (type I diabetes), uveitis, antireceptor disease, myastheniagravis, thyrotoxicosis, thyroiditis, Hashimoto's disease and the like.

In the present specification, the allergic disease includes, forexample, atopic dermatitis, asthma, rhinitis, conjunctivitis, hay feverand the like. As a preferable allergic disease, atopic dermatitis may becited.

In the present specification, the immunosuppressant means a drug whichis to be used for preventing and/or treating rejection intransplantation, autoimmune diseases, various malignant tumors, cancer,allergic diseases, etc. As such a drug, use may be made of anantimetabolite, an alkylating agent, a T cell activation inhibitor (a Tcell function suppressor), a calcineurin inhibitor, a proliferationsignal inhibitor, a steroid, an antibody used in immune suppression,other remedies for rejection and the like.

In the present specification, the agent causing lymphopenia means a drughaving effects of reducing lymphocytes in the peripheral blood, reducingcirculating lymphocytes, reducing the amount of permeated lymphocytes,promoting the lymphocytes homing into a secondary lymphatic tissue,suppressing the recirculation of lymphocytes from lymph nods into theblood, inhibiting an enzyme in the nucleic acid synthesis pathway oflymphocytes (the pyrimidine metabolic system and the purine metabolicsystem) and the like.

In the present specification, the secondary lymphatic tissue includes,for example, lymph nods, Peyer's patch (an intestinal lymphatic tissue),spleen and the like.

In the present specification, the effect of promoting the lymphocyteshoming into a secondary lymphatic tissue means promotion of themigration of lymphocytes into a secondary lymphatic tissue, enhancementof the separation of lymphocytes in a secondary lymphatic tissue,prolongation of the sustention of lymphocytes in a secondary lymphatictissue and the like. Owing to these effects, lymphocytes can be reducedin a site suffering from inflammation or rejection, etc.

In the present specification, the effect of protecting lymphocytes inthe peripheral blood during cancer therapy means an effect ofpreliminarily homing lymphocytes in the peripheral blood into asecondary lymphatic tissue before a cancer therapy (in particular,chemotherapy, radiotherapy, etc.) to thereby protect the lymphocytes.This effect includes the protection of lymphocytes inpre-transplantation step of administering a large amount of ananticancer agent. It is known that the treatment of cancer by achemotherapy, etc. with the use of an anticancer agent is accompanied byserious side effects such as the hypofunction of hematopoietic cells,thereby making a patient infectible. Such side effects can be lessenedby the above-described function.

In the present specification, the cyclic group is, for example, acarbocyclic group or a heterocyclic group.

In the present specification, the carbocyclic group is, for example, aC3-15 carbocyclic group. The C3-15 carbocyclic group includes C3-15mono-, bi- or tricyclic carbocyclic aryl, a partially or fully saturatedcarbocyclic group, a bicyclic carbocyclic group having a spiro bond anda bridged bicyclic carbocyclic group. Examples include cyclopropane,cyclobutane, cyclopentane, cyclohexane, cycloheptane, cyclooctane,cyclononane, cyclodecane, cycloundecane, cyclododecane,cyclotridodecane, cyclotetradecane, cyclopentadecane, cyclopentene,cyclohexene, cycloheptene, cyclooctene, cyclopentadiene, cyclohexadiene,cycloheptadiene, cyclooctadiene, benzene, pentalene, perhydropentalene,azulene, perhydroazulene, indene, perhydroindene, indane, naphthalene,dihydronaphthalene, tetrahydronaphthalene, perhydronaphthalene,6,7-dihydro-5H-benzo[7]annulene, 5H-benzo[7]annulene, heptalene,perhydroheptalene, biphenylene, as-indacene, s-indacene, acenaphthylene,acenaphthene, fluorene, phenalene, phenanthrene, anthracene,spiro[4.4]nonane, spiro[4.5]decane, spiro[5.5]undecane,bicyclo[2.2.1]heptane, bicyclo[2.2.1]hept-2-ene, bicyclo[3.1.1]heptane,bicyclo[3.1.1]hept-2-ene, bicyclo[2.2.2]octane, bicyclo[2.2.2]oct-2-ene,adamantane, and noradamantane rings, and the like.

In the present specification, the C5-12 monocyclic or bicycliccarbocyclic group is, for example, C5-12 monocyclic or bicycliccarbocyclic aryl which partially or fully saturated. Examples includecyclopentane, cyclohexane, cycloheptane, cyclooctane, cyclononane,cyclodecane, cycloundecane, cyclododecane, cyclotridodecane,cyclotetradecane, cyclopentadecane, cyclopentene, cyclohexene,cycloheptene, cyclooctene, cyclopentadiene, cyclohexadiene,cycloheptadiene, cyclooctadiene, benzene, pentalene, perhydropentalene,azulene, perhydroazulene, indene, perhydroindene, indane, naphthalene,dihydronaphthalene, tetrahydronaphthalene, perhydronaphthalene,6,7-dihydro-5H-benzo[7]annulene, 5H-benzo[7]annulene, heptalene, andperhydroheptalene rings, and the like.

In the present specification, the C5-7 monocyclic carbocyclic group is,for example, a C5-7 monocyclic carbocyclic aryl which may partially orfully saturated. Examples include cyclopentane, cyclohexane,cycloheptane, cyclopentene, cyclohexene, cycloheptene, cyclopentadiene,cyclohexadiene, cycloheptadiene, and benzene rings, and the like.

In the present specification, the heterocyclic group is, for example, a3- to 15-membered heterocyclic group containing 1 to 5 hetero atomsselected from an oxygen atom, a nitrogen atom and a sulfur atom. The 3-to 15-membered heterocyclic group containing 1 to 5 hetero atomsselected from an oxygen atom, a nitrogen atom and a sulfur atomincludes, for example, a 3- to 15-membered, monocyclic, bicyclic ortricyclic heterocyclic aryl, a bicyclic heterocyclic group having aspiro bond and a bridged bicyclic heterocyclic group, which eachcontains 1 to 5 hetero atoms selected from an oxygen atom, a nitrogenatom and a sulfur atom and may be partially or fully saturated. Examplesincludes pyrrole, imidazole, triazole, tetrazole, pyrazole, pyridine,pyrazine, pyrimidine, pyridazine, azepine, diazepine, furan, pyran,oxepine, thiophene, thiopyran, thiepine, oxazole, isoxazole, thiazole,isothiazole, furazane, oxadiazole, oxazine, oxadiazine, oxazepine,oxadiazepine, thiadiazole, thiazine, thiadiazine, thiazepine,thiadiazepine, indole, isoindole, indolizine, benzofuran, isobenzofuran,benzothiophene, isobenzothiophene, dithianaphthalene, indazole,quinoline, isoquinoline, quinolizine, purine, phthalazine, pteridine,naphthyridine, quinoxaline, quinazoline, cinnoline, benzoxazole,benzothiazole, benzimidazole, chromene, benzoxepine, benzoxazepine,benzoxadiazepine, benzothiepine, benzothiazepine, benzothiadiazepine,benzazepine, benzodiazepine, benzofurazane, benzothiadiazole,benzotriazole, carbazole, β-carboline, acridine, phenazine,dibenzofuran, xanthene, dibenzothiophene, phenothiazine, phenoxazine,phenoxathiin, thianthrene, phenanthridine, phenanthroline, perimidine,aziridine, azetidine, pyrroline, pyrrolidine, imidazoline,imidazolidine, triazoline, triazolidine, tetrazoline, tetrazolidine,pyrazoline, pyrazolidine, dihydropyridine, tetrahydropyridine,piperidine, dihydropyrazine, tetrahydropyrazine, piperazine,dihydropyrimidine, tetrahydropyrimidine, perhydropyrimidine,dihydropyridazine, tetrahydropyridazine, perhydropyridazine,dihydroazepine, tetrahydroazepine, perhydroazepine, dihydrodiazepine,tetrahydrodiazepine, perhydrodiazepine, oxirane, oxetane, dihydrofuran,tetrahydrofuran, dihydropyran, tetrahydropyran, dihydrooxepine,tetrahydrooxepine, perhydrooxepine, thiirane, thietane,dihydrothiophene, tetrahydrothiophene, dihydrothiopyran,tetrahydrothiopyran, dihydrothiepine, tetrahydrothiepine,perhydrothiepine, dihydrooxazole, tetrahydrooxazole (oxazolidine),dihydroisoxazole, tetrahydroisoxazole (isoxazolidine), dihydrothiazole,tetrahydrothiazole (thiazolidine), dihydroisothiazole,tetrahydroisothiazole (isothiazolidine), dihydrofurazane,tetrahydrofurazane, dihydrooxadiazole, tetrahydrooxadiazole(oxadiazolidine), dihydrooxazine, tetrahydrooxazine, dihydrooxadiazine,tetrahydrooxadiazine, dihydrooxazepine, tetrahydrooxazepine,perhydrooxazepine, dihydrooxadiazepine, tetrahydrooxadiazepine,perhydrooxadiazepine, dihydrothiadiazole, tetrahydrothiadiazole(thiadiazolidine), dihydrothiazine, tetrahydrothiazine,dihydrothiadiazine, tetrahydrothiadiazine, dihydrothiazepine,tetrahydrothiazepine, perhydrothiazepine, dihydrothiadiazepine,tetrahydrothiadiazepine, perhydrothiadiazepine, morpholine,thiomorpholine, oxathiane, indoline, isoindoline, dihydrobenzofuran,perhydrobenzofuran, dihydroisobenzofuran, perhydroisobenzofuran,dihydrobenzothiophene, perhydrobenzothiophene, dihydroisobenzothiophene,perhydroisobenzothiophene, dihydroindazole, perhydroindazole,dihydroquinoline, tetrahydroquinoline, perhydroquinoline,dihydroisoquinoline, tetrahydroisoquinoline, perhydroisoquinoline,dihydrophthalazine, tetrahydrophthalazine, perhydrophthalazine,dihydronaphthyridine, tetrahydronaphthyridine, perhydronaphthyridine,dihydroquinoxaline, tetrahydroquinoxaline, perhydroquinoxaline,dihydroquinazoline, tetrahydroquinazoline, perhydroquinazoline,dihydrocinnoline, tetrahydrocinnoline, perhydrocinnoline,benzooxathiane, dihydrobenzooxazine, dihydrobenzothiazine,pyrazinomorpholine, dihydrobenzoxazole, perhydrobenzoxazole,dihydrobenzothiazole, perhydrobenzothiazole, dihydrobenzimidazole,perhydrobenzimidazole, dihydrobenzazepine, tetrahydrobenzazepine,dihydrobenzodiazepine, tetrahydrobenzodiazepine, benzodioxepane,dihydrobenzoxazepine, tetrahydrobenzoxazepine, dihydrocarbazole,tetrahydrocarbazole, perhydrocarbazole, dihydroacridine,tetrahydroacridine, perhydroacridine, dihydrodibenzofuran,dihydrodibenzothiophene, tetrahydrodibenzofuran,tetrahydrodibenzothiophene, perhydrodibenzofuran,perhydrodibenzothiophene, dioxolane, dioxane, dithiolane, dithiane,dioxaindan, benzodioxane, chromene, chroman, benzodithiolane, andbenzodithiane rings, and the like.

In the present specification, the 5- to 12-membered, monocyclic orbicyclic heterocyclic aryl, which contains 1 to 3 hetero atoms selectedfrom an oxygen atom, a nitrogen atom and a sulfur atom and may bepartially or fully saturated is, for example, 5- to 12-memberedmonocyclic or bicyclic heterocyclic aryl, a bicyclic heterocyclic grouphaving a spiro bond or a bridged bicyclic heterocyclic group, which eachcontains 1 to 3 hetero atoms selected from an oxygen atom, a nitrogenatom and a sulfur atom and may be partially or fully saturated. Examplesinclude pyrrole, imidazole, triazole, pyrazole, pyridine, pyrazine,pyrimidine, pyridazine, azepine, diazepine, furan, pyran, oxepine,thiophene, thiopyran, thiepine, oxazole, isoxazole, thiazole,isothiazole, furazane, oxadiazole, oxazine, oxadiazine, oxazepine,oxadiazepine, thiadiazole, thiazine, thiadiazine, thiazepine,thiadiazepine, indole, isoindole, indolizine, benzofuran, isobenzofuran,benzothiophene, isobenzothiophene, dithianaphthalene, indazole,quinoline, isoquinoline, quinolizine, phthalazine, naphthyridine,quinoxaline, quinazoline, cinnoline, benzoxazole, benzothiazole,benzimidazole, chromene, benzoxepine, dihydrobenzoxepine, benzoxazepine,benzoxadiazepine, benzothiepine, benzothiazepine, benzothiadiazepine,benzazepine, benzodiazepine, benzofurazane, benzothiadiazole,benzotriazole, pyrroline, pyrrolidine, imidazoline, imidazolidine,triazoline, triazolidine, pyrazoline, pyrazolidine, dihydropyridine,tetrahydropyridine, piperidine, dihydropyrazine, tetrahydropyrazine,piperazine, dihydropyrimidine, tetrahydropyrimidine, perhydropyrimidine,dihydropyridazine, tetrahydropyridazine, perhydropyridazine,dihydroazepine, tetrahydroazepine, perhydroazepine, dihydrodiazepine,tetrahydrodiazepine, perhydrodiazepine, dihydrofuran, tetrahydrofuran,dihydropyran, tetrahydropyran, dihydrooxepine, tetrahydrooxepine,perhydrooxepine, dihydrothiophene, tetrahydrothiophene,dihydrothiopyran, tetrahydrothiopyran, dihydrothiepine,tetrahydrothiepine, perhydrothiepine, dihydrooxazole, tetrahydrooxazole(oxazolidine), dihydroisoxazole, tetrahydroisoxazole (isoxazolidine),dihydrothiazole, tetrahydrothiazole (thiazolidine), dihydroisothiazole,tetrahydroisothiazole (isothiazolidine), dihydrofurazane,tetrahydrofurazane, dihydrooxadiazole, tetrahydrooxadiazole(oxadiazolidine), dihydrooxazine, tetrahydrooxazine, dihydrooxadiazine,tetrahydrooxadiazine, dihydrooxazepine, tetrahydrooxazepine,perhydrooxazepine, dihydrooxadiazepine, tetrahydrooxadiazepine,perhydrooxadiazepine, dihydrothiadiazole, tetrahydrothiadiazole(thiadiazolidine), dihydrothiazine, tetrahydrothiazine,dihydrothiadiazine, tetrahydrothiadiazine, dihydrothiazepine,tetrahydrothiazepine, perhydrothiazepine, dihydrothiadiazepine,tetrahydrothiadiazepine, perhydrothiadiazepine, morpholine,thiomorpholine, oxathiane, indoline, isoindoline, dihydrobenzofuran,perhydrobenzofuran, dihydroisobenzofuran, perhydroisobenzofuran,dihydrobenzothiophene, perhydrobenzothiophene, dihydroisobenzothiophene,perhydroisobenzothiophene, dihydroindazole, perhydroindazole,dihydroquinoline, tetrahydroquinoline, perhydroquinoline,dihydroisoquinoline, tetrahydroisoquinoline, perhydroisoquinoline,dihydrophthalazine, tetrahydrophthalazine, perhydrophthalazine,dihydronaphthyridine, tetrahydronaphthyridine, perhydronaphthyridine,dihydroquinoxaline, tetrahydroquinoxaline, perhydroquinoxaline,dihydroquinazoline, tetrahydroquinazoline, perhydroquinazoline,dihydrocinnoline, tetrahydrocinnoline, perhydrocinnoline,benzooxathiane, dihydrobenzooxazine, dihydrobenzothiazine,pyrazinomorpholine, dihydrobenzoxazole, perhydrobenzoxazole,dihydrobenzothiazole, perhydrobenzothiazole, dihydrobenzimidazole,perhydrobenzimidazole, dihydrobenzazepine, tetrahydrobenzazepine,dihydrobenzodiazepine, tetrahydrobenzodiazepine, benzodioxepane,dihydrobenzoxazepine, tetrahydrobenzoxazepine, dioxolane, dioxane,dithiolane, dithiane, dioxaindan, benzodioxane, chroman,benzodithiolane, and benzodithiane rings, and the like.

In the present specification, the 5- to 7-membered monocyclicheterocyclic group containing one or two nitrogen atoms, one oxygen atomand/or one sulfur atom is, for example, a 5- to 7-membered monocyclicheterocyclic aryl containing one or two nitrogen atoms, one oxygen atomand/or one sulfur atom, which may be partially or fully saturated.Examples include pyrrole, imidazole, pyrazole, pyridine, pyrazine,pyrimidine, pyridazine, azepine, diazepine, furan, pyran, oxepine,thiophene, thiaine (thiopyran), thiepine, oxazole, isoxazole, thiazole,isothiazole, furazane, oxadiazole, oxazine, oxadiazine, oxazepine,oxadiazepine, thiadiazole, thiazine, thiadiazine, thiazepine,thiadiazepine, pyrroline, pyrrolidine, imidazoline, imidazolidine,pyrazoline, pyrazolidine, dihydropyridine, tetrahydropyridine,piperidine, dihydropyrazine, tetrahydropyrazine, piperazine,dihydropyrimidine, tetrahydropyrimidine, perhydropyrimidine,dihydropyridazine, tetrahydropyridazine, perhydropyridazine,dihydroazepine, tetrahydroazepine, perhydroazepine, dihydrodiazepine,tetrahydrodiazepine, perhydrodiazepine, dihydrofuran, tetrahydrofuran,dihydropyran, tetrahydropyran, dihydrothiophene, tetrahydrothiophene,dihydrothiaine (dihydrothiopyran), tetrahydrothiaine(tetrahydrothiopyran), dihydrooxazole, tetrahydrooxazole,dihydroisoxazole, tetrahydroisoxazole, dihydrothiazole,tetrahydrothiazole, dihydroisothiazole, tetrahydroisothiazole,dihydrooxadiazole, tetrahydrooxadiazole, dihydrothiodiazole,tetrahydrothiodiazole, tetrahydrooxadiazine, tetrahydrothiadiazine,tetrahydrooxazepine, tetrahydrooxadiazepine, perhydrooxazepine,perhydrooxadiazepine, tetrahydrothiazepine, tetrahydrothiadiazepine,perhydrothiazepine, perhydrothiadiazepine, morpholine, andthiomorpholine rings, and the like.

In the present specification, the 5- to 7-membered monocyclicheterocyclic group containing one or two nitrogen atoms, one oxygen atomand/or one sulfur atom, formed by substituents and a nitrogen atom boundthereto is, for example, a 5- to 7-membered monocyclic heterocyclic arylcontaining one or two nitrogen atoms, one oxygen atom and/or one sulfuratom, which may be partially or fully saturated. Examples includepyrrole, imidazole, pyrazole, pyrroline, pyrrolidine, imidazoline,imidazolidine, pyrazoline, pyrazolidine, dihydropyridine,tetrahydropyridine, piperidine, dihydropyrazine, tetrahydropyrazine,piperazine, dihydropyrimidine, tetrahydropyrimidine, perhydropyrimidine,dihydropyridazine, tetrahydropyridazine, perhydropyridazine,dihydroazepine, tetrahydroazepine, perhydroazepine, dihydrodiazepine,tetrahydrodiazepine, perhydrodiazepine, tetrahydrooxazole,tetrahydroisoxazole, tetrahydrothiazole, tetrahydroisothiazole,dihydrooxadiazole, tetrahydrooxadiazole, dihydrothiodiazole,tetrahydrothiodiazole, tetrahydrooxadiazine, tetrahydrothiadiazine,tetrahydrooxadiazepine, perhydrooxazepine, perhydrooxadiazepine,tetrahydrothiadiazepine, perhydrothiazepine, perhydrothiadiazepine,morpholine, and thiomorpholine rings, and the like.

In the present specification, the cyclic group in the cyclic group whichmay further have a substituent(s), the cyclic group which may besubstituted and “substituted with a cyclic group” has the same meaningas the cyclic group described above.

In the present specification, the substituent in “which may have asubstituent(s)” is not particularly limited, so long as it is asubstituent. Examples include C1-20 alkyl which may be substituted,C2-20 alkenyl which may be substituted, C2-20 alkynyl which may besubstituted, C1-20 alkylidene which may be substituted, a cyclic groupwhich may be substituted, oxo, hydroxy, C1-20 alkyloxy which may besubstituted, C2-20 alkenyloxy which may be substituted, C2-20 alkynyloxywhich may be substituted, hydroxy which may be protected by a cyclicgroup which may be substituted, C1-20 acyloxy which may be substituted,thioxo, mercapto, C1-20 alkylthio which may be substituted, C2-20alkenylthio which may be substituted, C2-20 alkynylthio which may besubstituted, mercapto substituted with a cyclic group which may besubstituted, C1-20 alkylsulfinyl which may be substituted, C2-20alkenylsulfinyl which may be substituted, C2-20 alkynylsulfinyl whichmay be substituted, sulfinyl substituted with a cyclic group which maybe substituted, C1-20 alkylsulfonyl which may be substituted, C2-20alkenylsulfonyl which may be substituted, C2-20 alkynylsulfonyl whichmay be substituted, sulfonyl substituted with a cyclic group which maybe substituted, sulfino which may be substituted, sulfo which may besubstituted, sulfamoyl which may be substituted (when the substituentsare two, they may be taken together with a nitrogen atom to which theyare bound to form a 5- to 7-membered monocyclic heterocyclic groupcontaining one or two nitrogen atoms, one oxygen atom and/or one sulfuratom (this heterocyclic group may be substituted with C1-8 alkyl,hydroxy or amino)), carbonyl which may be substituted, carboxy which maybe substituted, C1-20 acyl which may be substituted, carbamoyl which maybe substituted (when the substituents are two, they may be takentogether with a nitrogen atom to which they are bound to form a 5- to7-membered monocyclic heterocyclic group containing one or two nitrogenatoms, one oxygen atom and/or one sulfur atom (this heterocyclic groupmay be substituted with C1-8 alkyl, hydroxy or amino)), cyano, amidinowhich may be substituted (when the substituents are two, they may betaken together with a nitrogen atom to which they are bound to form a 5-to 7-membered monocyclic heterocyclic group containing one or twonitrogen atoms, one oxygen atom and/or one sulfur atom (thisheterocyclic group may be substituted with C1-8 alkyl, hydroxy oramino)), nitro, nitroso, imino which may be substituted, amino which maybe substituted (when the substituents are two, they may be takentogether with a nitrogen atom to which they are bound to form a 5- to7-membered monocyclic heterocyclic group containing one or two nitrogenatoms, one oxygen atom and/or one sulfur atom (this heterocyclic groupmay be substituted with C1-8 alkyl, hydroxy or amino)), a halogen atomand the like.

In the present specification, the substituent represented by R¹, R⁷,R²⁷, R²⁹, R³⁰ and R³¹ has the same meaning as the substituent in thecyclic group which may further have a substituent(s) described above.

In the present specification, the substituent in “which may besubstituted” is, for example, C1-20 alkyl, C2-20 alkenyl, C2-20 alkynyl,C1-20 alkylidene, a cyclic group, C1-20 alkyl substituted with a cyclicgroup, oxo, hydroxy, C1-20 alkyloxy, C2-20 alkenyloxy, C2-20 alkynyloxy,hydroxy which may be protected by a cyclic group, C1-20 acylthio,thioxo, mercapto, C1-20 alkylthio, C2-20 alkenylthio, C2-20 alkynylthio,mercapto substituted with a cyclic group, C1-20 alkylsulfinyl, C2-20alkenylsulfinyl, C2-20 alkynylsulfinyl, sulfinyl substituted with acyclic group, C1-20 alkylsulfonyl, C2-20 alkenylsulfonyl, C2-20alkynylsulfonyl, sulfonyl substituted with a cyclic group, C1-20alkylsulfonyl substituted with a cyclic group, sulfino, sulfo,sulfamoyl, carboxy, C1-20 acyl, C1-20 acyl substituted with a cyclicgroup, carbonyl substituted with a cyclic group, carbamoyl, cyano,amidino, nitro, nitroso, imino, amino, a halogen atom or the like. Theyare substituted at any position which can be substituted with any numberwhich can be substituted.

In the present specification, the C1-20 alkyl includes, for example,methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl,decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl,heptadecyl, octadecyl, nonadecyl, icosyl, and isomers thereof.

In the present specification, the C1-8 alkyl includes, for example,methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, and isomersthereof.

In the present specification, the C2-20 alkenyl includes, for example,ethenyl, propenyl, butenyl, pentenyl, hexenyl, heptenyl, octenyl,nonenyl, decenyl, undecenyl, dodecenyl, tridecenyl, tetradecenyl,pentadecenyl, hexadecenyl, heptadecenyl, octadecenyl, nonadecenyl,icosenyl, and isomers thereof.

In the present specification, the C2-20 alkynyl includes, for example,ethynyl, propynyl, butynyl, pentynyl, hexynyl, heptynyl, octynyl,nonynyl, decynyl, undecynyl, dodecynyl, tridecynyl, tetradecynyl,pentadecynyl, hexadecynyl, heptadecynyl, octadecynyl, nonadecynyl,icosynyl, and isomers thereof.

In the present specification, the C1-20 alkylidene includes, forexample, methylidene, ethylidene, propylidene, butylidene, pentylidene,hexylidene, heptylidene, octylidene, nonylidene, decylidene,undecylidene, dodecylidene, tridecylidene, tetradecylidene,pentadecylidene, hexadecylidene, heptadecylidene, octadecylidene,nonadecylidene, icosylidene, and isomers thereof.

In the present specification, the C1-20 alkyloxy includes, for example,methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, heptyloxy,octyloxy, nonyloxy, decyloxy, undecyloxy, dodecyloxy, tridecyloxy,tetradecyloxy, pentadecyloxy, hexadecyloxy, heptadecyloxy, octadecyloxy,nonadecyloxy, icosyloxy, and isomers thereof.

In the present specification, the C1-8 alkoxy includes, for example,methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, heptyloxy,octyloxy, and isomers thereof.

In the present specification, the C2-20 alkenyloxy includes, forexample, ethenyloxy, propenyloxy, butenyloxy, pentenyloxy, hexenyloxy,heptenyloxy, octenyloxy, nonenyloxy, decenyloxy, undecenyloxy,dodecenyloxy, tridecenyloxy, tetradecenyloxy, pentadecenyloxy,hexadecenyloxy, heptadecenyloxy, octadecenyloxy, nonadecenyloxy,icosenyloxy, and isomers thereof.

In the present invention, the C2-20 alkynyloxy includes, for example,ethynyloxy, propynyloxy, butynyloxy, pentynyloxy, hexynyloxy,heptynyloxy, octynyloxy, nonynyloxy, decynyloxy, undecynyloxy,dodecynyloxy, tridecynyloxy, tetradecynyloxy, pentadecynyloxy,hexadecynyloxy, heptadecynyloxy, octadecynyloxy, nonadecynyloxy,icosynyloxy, and isomers thereof.

In the present specification, the C1-20 alkylthio includes, for example,methylthio, ethylthio, propylthio, butylthio, pentylthio, hexylthio,heptylthio, octylthio, nonylthio, decylthio, undecylthio, dodecylthio,tridecylthio, tetradecylthio, pentadecylthio, hexadecylthio,heptadecylthio, octadecylthio, nonadecylthio, icosylthio, and isomersthereof.

In the present specification, the C2-20 alkenylthio includes, forexample, ethenylthio, propenylthio, butenylthio, pentenylthio,hexenylthio, heptenylthio, octenylthio, nonenylthio, decenylthio,undecenylthio, dodecenylthio, tridecenylthio, tetradecenylthio,pentadecenylthio, hexadecenylthio, heptadecenylthio, octadecenylthio,nonadecenylthio, icosenylthio, and isomers thereof.

In the present specification, the C2-20 alkynylthio includes, forexample, ethynylthio, propynylthio, butynylthio, pentynylthio,hexynylthio, heptynylthio, octynylthio, nonynylthio, decynylthio,undecynylthio, dodecynylthio, tridecynylthio, tetradecynylthio,pentadecynylthio, hexadecynylthio, heptadecynylthio, octadecynylthio,nonadecynylthio, icosynylthio, and isomers thereof.

In the present specification, the C1-20 alkylsulfinyl includes, forexample, methylsulfinyl, ethylsulfinyl, propylsulfinyl, butylsulfinyl,pentylsulfinyl, hexylsulfinyl, heptylsulfinyl, octylsulfinyl,nonylsulfinyl, decylsulfinyl, undecylsulfinyl, dodecylsulfinyl,tridecylsulfinyl, tetradecylsulfinyl, pentadecylsulfinyl,hexadecylsulfinyl, heptadecylsulfinyl, octadecylsulfinyl,nonadecylsulfinyl, icosylsulfinyl, and isomers thereof.

In the present specification, the C2-20 alkenylsulfinyl includes, forexample, ethenylsulfinyl, propenylsulfinyl, butenylsulfinyl,pentenylsulfinyl, hexenylsulfinyl, heptenylsulfinyl, octenylsulfinyl,nonenylsulfinyl, decenylsulfinyl, undecenylsulfinyl, dodecenylsulfinyl,tridecenylsulfinyl, tetradecenylsulfinyl, pentadecenylsulfinyl,hexadecenylsulfinyl, heptadecenylsulfinyl, octadecenylsulfinyl,nonadecenylsulfinyl, icosenylsulfinyl, and isomers thereof.

In the present specification, the C2-20 alkynylsulfinyl includes, forexample, ethynylsulfinyl, propynylsulfinyl, butynylsulfinyl,pentynylsulfinyl, hexynylsulfinyl, heptynylsulfinyl, octynylsulfinyl,nonynylsulfinyl, decynylsulfinyl, undecynylsulfinyl, dodecynylsulfinyl,tridecynylsulfinyl, tetradecynyl sulfinyl, pentadecynylsulfinyl,hexadecynylsulfinyl, heptadecynylsulfinyl, octadecynylsulfinyl,nonadecynylsulfinyl, icosynylsulfinyl, and isomers thereof.

In the present specification, the C1-20 alkylsulfonyl includes, forexample, methylsulfonyl, ethylsulfonyl, propylsulfonyl, butylsulfonyl,pentylsulfonyl, hexylsulfonyl, heptylsulfonyl, octylsulfonyl,nonylsulfonyl, decylsulfonyl, undecylsulfonyl, dodecylsulfonyl,tridecylsulfonyl, tetradecylsulfonyl, pentadecylsulfonyl,hexadecylsulfonyl, heptadecylsulfonyl, octadecylsulfonyl,nonadecylsulfonyl, icosylsulfonyl, and isomers thereof.

In the present specification, the C2-20 alkenylsulfonyl includes, forexample, ethenylsulfonyl, propenylsulfonyl, butenylsulfonyl,pentenylsulfonyl, hexenylsulfonyl, heptenylsulfonyl, octenylsulfonyl,nonenylsulfonyl, decenylsulfonyl, undecenylsulfonyl, dodecenylsulfonyl,tridecenylsulfonyl, tetradecenylsulfonyl, pentadecenylsulfonyl,hexadecenylsulfonyl, heptadecenylsulfonyl, octadecenylsulfonyl,nonadecenylsulfonyl, icosenylsulfonyl, and isomers thereof.

In the present specification, the C2-20 alkynylsulfonyl includes, forexample, ethynylsulfonyl, propynylsulfonyl, butynylsulfonyl,pentynylsulfonyl, hexynylsulfonyl, heptynylsulfonyl, octynylsulfonyl,nonynylsulfonyl, decynylsulfonyl, undecynylsulfonyl, dodecynylsulfonyl,tridecynylsulfonyl, tetradecynylsulfonyl, pentadecynylsulfonyl,hexadecynylsulfonyl, heptadecynylsulfonyl, octadecynylsulfonyl,nonadecynylsulfonyl, icosynylsulfonyl, and isomers thereof.

In the present specification, the C1-20 acyl includes, for example,methanoyl, ethanoyl, propanoyl, butanoyl, pentanoyl, hexanoyl,heptanoyl, octanoyl, nonanoyl, decanoyl, undecanoyl, dodecanoyl,tridecanoyl, tetradecanoyl, pentadecanoyl, hexadecanoyl, heptadecanoyl,octadecanoyl, nonadecanoyl, icosanoyl, and isomers thereof.

In the present specification, the C1-20 acyloxy includes, for example,methanoyloxy, ethanoyloxy, propanoyloxy, butanoyloxy, pentanoyloxy,hexanoyloxy, heptanoyloxy, octanoyloxy, nonanoyloxy, decanoyloxy,undecanoyloxy, dodecanoyloxy, tridecanoyloxy, tetradecanoyloxy,pentadecanoyloxy, hexadecanoyloxy, heptadecanoyloxy, octadecanoyloxy,nonadecanoyloxy, icosanoyloxy, and isomers thereof.

In the present specification, the protecting group for hydroxy which maybe protected has the same meaning as the substituent for “which may besubstituted” described above.

In the present specification, the halogen atom includes, for example,fluorine, chlorine, bromine and iodine.

In the present specification, the bond means that the atoms are directlybound through no other atom.

In the present specification, the spacer having 1 to 10 atoms in itsmain chain means spacing in which 1 to 10 atoms are continuously linkedin its main chain. In this case, the number of atoms as a main chainshould be counted such that the atoms in its main chain become minimum.The spacer having 1 to 10 atoms in its main chain includes, for example,a divalent group having 1 to 10 atoms in its main chain which is 1 to 4combinations selected from C1-10 alkylene which may lie substituted,C2-10 alkenylene which may be substituted, C2-10 alkynylene which may besubstituted, a nitrogen atom which may be substituted (—NH—), —CO—, —O—,—S—, —SO—, —SO₂—, -(carbocyclic group which may be substituted)-,-(heterocyclic group which may be substituted)-, and the like.

In the present specification, the C1-10 alkylene includes, for example,methylene, ethylene, trimethylene, tetramethylene, pentamethylene,hexamethylene, heptamethylene, octamethylene, nonamethylene,decamethylene, and isomers thereof.

In the present specification, the C2-10 alkenylene includes, forexample, ethenylene, propenylene, butenylene, pentenylene, hexenylene,heptenylene, octenylene, nonenylene, decenylene, and isomers thereof.

In the present specification, the C2-10 alkynylene includes, forexample, ethynylene, propynylene, butynylene, pentynylene, hexynylene,heptynylene, octynylene, nonynylene, decynylene, and isomers thereof.

In the present specification, the spacer having 1 to 9 atoms in its mainchain means spacing in which 1 to 9 atoms are continuously linked in itsmain chain. In this case, the number of atoms as a main chain should becounted such that the atoms in its main chain become minimum. The spacerhaving 1 to 9 atoms in its main chain includes, for example, a divalentgroup having 1 to 9 atoms in its main chain which is 1 to 4 combinationsselected from C1-9 alkylene which may be substituted, C2-9 alkenylenewhich may be substituted, C2-9 alkynylene which may be substituted, anitrogen atom which may be substituted (—NH—), —CO—, —O—, —S—, —SO—,—SO₂—, -(carbocyclic group which may be substituted)-, -(heterocyclicgroup which may be substituted)-, and the like.

In the present specification, the C1-9 alkylene includes, for example,methylene, ethylene, trimethylene, tetramethylene, pentamethylene,hexamethylene, heptamethylene, octamethylene, nonamethylene, and isomersthereof.

In the present specification, the C2-9 alkenylene includes, for example,ethenylene, propenylene, butenylene, pentenylene, hexenylene,heptenylene, octenylene, nonenylene, and isomers thereof.

In the present specification, the C2-9 alkynylene includes, for example,ethynylene, propynylene, bytynylene, pentynylene, hexynylene,heptynylene, octynylene, nonylene, and isomers thereof.

In the present specification, the spacer having 1 to 8 atoms in its mainchain means spacing in which 1 to 9 atoms are continuously linked in itsmain chain. In this case, the number of atoms as a main chain should becounted such that the atoms in its main chain become minimum. The spacerhaving 1 to 8 atoms in its main chain includes, for example, a divalentgroup having 1 to 8 atoms in its main chain which is 1 to 4 combinationsselected from C1-8 alkylene which may be substituted, C2-8 alkenylenewhich may be substituted, C2-8 alkynylene which may be substituted, anitrogen atom which may be substituted (—NH—), —CO—, —O—, —S—, —SO—,—SO₂—, -(carbocyclic group which may be substituted)-, -(heterocyclicgroup which may be substituted)-, and the like.

In the present specification, the C1-8 alkylene includes, for example,methylene, ethylene, trimethylene, tetramethylene, pentamethylene,hexamethylene, heptamethylene, octamethylene, and isomers thereof.

In the present specification, the C2-8 alkenylene, includes, forexample, ethenylene, propenylene; butenylene, pentenylene, hexenylene,heptenylene, octenylene, and isomers thereof.

In the present specification, the C2-8 alkynylene includes, for example,ethynylene, propynylene, bytynylene, pentynylene, hexynylene,heptynylene, octynylene, and isomers thereof.

In the present specification, the C1-3 alkylene includes, for example,methylene, ethylene, trimethylene, and isomers thereof.

In the present specification, the C3-6 cycloalkylene includes, forexample, cyclopropylene, cyclobutylene, cyclopenylene, cyclohexylene,and isomers thereof.

In the present specification, the ring group which may have asubstituent(s) formed by taking one atom in the spacer represented by Xtogether with a substituent on ring B means a ring group which may havea substituent(s) formed by taking one atom in the spacer represented byX together with one substituent on ring B. The ring group which may havea substituent(s) has the same meaning as the cyclic group which mayfurther have a substituent(s).

In the present specification, the ring group which may have asubstituent(s) formed by taking one atom in the spacer represented by Ytogether with a substituent on ring B means a ring group which may havea substituent(s) formed by taking one atom in the spacer represented byY together with one substituent on ring B. The ring group which may havea substituent(s) has the same meaning as the cyclic group which mayfurther have a substituent(s).

In the present specification, the nitrogen-containing heterocyclic groupwhich may have a substituent(s) formed by taking one atom in the spacerrepresented by Y¹ and/or Y² together with R⁷ means a nitrogen-containingheterocyclic group which may have a substituent(s) formed by taking oneatom in the spacer represented by Y¹ and/or Y² together with R⁷ and anitrogen atom to which Y¹ or Y² is bound. The nitrogen-containingheterocyclic group in the nitrogen-containing heterocyclic group whichmay have a substituent(s) includes, for example, a 3- to 15-memberedheterocyclic group which contain one nitrogen atom and may furthercontain 1 to 4 hetero atoms selected from an oxygen atom, a nitrogenatom and a sulfur atom, and the like. The 3- to 15-membered heterocyclicgroup which contain one nitrogen atom and may further contain 1 to 4hetero atoms selected from an oxygen atom, a nitrogen atom and a sulfuratom includes a 3- to 15-membered monocyclic, bicyclic or tricyclicheterocyclic aryl, a bicyclic heterocyclic group and a bridged bicyclicheterocyclic group, which each contains one nitrogen atom, may furthercontain 1 to 4 hetero atoms selected from an oxygen atom, a nitrogenatom and a sulfur atom, and may be partially or fully saturated.Examples include pyrrole, imidazole, triazole, tetrazole, pyrazole,azepine, diazepine, indole, isoindole, indazole, purine,pyrrolopyridine, benzimidazole, benzazepine, benzodiazepine,benzotriazole, carbazole, β-carboline, phenothiazine, phenoxazine,pyrazoloisoquinoline, pyrazolonaphthyridine, pyrimidoindole,indolydinoindole, aziridine, azetidine, pyrroline, pyrrolidine,imidazoline, imidazolidine, triazoline, triazolidine, tetrazoline,tetrazolidine, pyrazoline, pyrazolidine, dihydropyridine,tetrahydropyridine, piperidine, dihydropyrazine, tetrahydropyrazine,piperazine, dihydropyrimidine, tetrahydropyrimidine, perhydropyrimidine,dihydropyridazine, tetrahydropyridazine, perhydropyridazine,dihydroazepine, tetrahydroazepine, perhydroazepine, dihydrodiazepine,tetrahydrodiazepine, perhydrodiazepine, dihydrooxazole,tetrahydrooxazole (oxazolidine), dihydroisoxazole, tetrahydroisoxazole(isoxazolidine), dihydrothiazole, tetrahydrothiazole (thiazolidine),dihydroisothiazole, tetrahydroisothiazole (isothiazolidine),dihydrofurazane, tetrahydrofurazane, dihydrooxadiazole,tetrahydrooxadiazole (oxadiazolidine), dihydrooxazine,tetrahydrooxazine, dihydrooxadiazine, tetrahydrooxadiazine,dihydrooxazepine, tetrahydrooxazepine, perhydrooxazepine,dihydrooxadiazepine, tetrahydrooxadiazepine, perhydrooxadiazepine,dihydrothiadiazole, tetrahydrothiadiazole (thiadiazolidine),dihydrothiazine, tetrahydrothiazine, dihydrothiadiazine,tetrahydrothiadiazine, dihydrothiazepine, tetrahydrothiazepine,perhydrothiazepine, dihydrothiadiazepine, tetrahydrothiadiazepine,perhydrothiadiazepine, morpholine, thiomorpholine, oxathiane, indoline,isoindoline, dihydroindazole, perhydroindazole, dihydroquinoline,tetrahydroquinoline, perhydroquinoline, dihydroisoquinoline,tetrahydroisoquinoline, perhydroisoquinoline, dihydrophthalazine,tetrahydrophthalazine, perhydrophthalazine, dihydronaphthyridine,tetrahydronaphthyridine, perhydronaphthyridine, dihydroquinoxaline,tetrahydroquinoxaline, perhydroquinoxaline, dihydroquinazoline,tetrahydroquinazoline, perhydroquinazoline, tetrahydropyrrolopyridine,dihydrocinnoline, tetrahydrocinnoline, perhydrocinnoline,dihydrobenzooxazine, dihydrobenzothiazine, pyrazinomorpholine,dihydrobenzoxazole, perhydrobenzoxazole, dihydrobenzothiazole,perhydrobenzothiazole, dihydrobenzimidazole, perhydrobenzimidazole,dihydrobenzazepine, tetrahydrobenzazepine(2,3,4,5-tetrahydro-1H-2-benzazepine,2,3,4,5-tetrahydro-1H-3-benzazepine, etc.), dihydrobenzodiazepine,tetrahydrobenzodiazepine, dihydrobenzoxazepine, tetrahydrobenzoxazepine,dihydrocarbazole, tetrahydrocarbazole, perhydrocarbazole,dihydroacridine, tetrahydroacridine, perhydroacridine,tetrapyridonaphthyridine, tetrahydro-β-carboline, dihydroazepinoindole,hexahydroazepinoindole, tetrahydropyrazoloisoquinoline,tetrahydropyrazolonaphthyridine, dihydroazepinoindazole,hexahydroazepinoindazole, dihydropyrazolopyridoazepine,hexahydropyrazolopyridoazepine, tetrahydropyrimidoindole,dihydrothiadinoindole, tetrahydrothiadinoindole, dihydrooxadinoindole,tetrahydrooxadinoindole, hexahydroindolydinoindole,dihydroindolobenzodiazepine, octahydroindoloquinolizine,hexahydroimidazopyridoindole, hexahydropyrrolothiazepinoindole,azaspiro[4.4]nonane, oxazaspiro[4.4]nonane, oxazaspiro[2.5]octane,azaspiro[4.5]decane, 1,3,8-triazaspiro[4.5]decane,2,7-diazaspiro[4.5]decane, 1,4,9-triazaspiro[5.5]undecane,oxazaspiro[4.5]decane, azaspiro[5.5]undecane, azabicyclo[2.2.1]heptane,azabicyclo[3.1.1]heptane, azabicyclo[3.2.1]octane(8-azabicyclo[3.2.1]octane, etc.), azabicyclo[2.2.2]octane(2-azabicyclo[2.2.2]octane, etc.), azabicyclo[2.1.1]hexane(5-azabicyclo[2.1.1]hexane, etc.), and the like.

In the present invention, the nitrogen-containing heterocyclic groupwhich may have a substituent(s) formed by taking one nitrogen atom inthe spacer represented by Y¹ together with a substituent on ring B meansthe same meaning as the above-described nitrogen-containing heterocyclicgroup which may have a substituent(s).

In the present invention, ring A is preferably a C3-15 carbocyclicgroup, more preferably a C5-12 monocyclic or bicyclic carbocyclic group,and more preferably a benzene, indane, indene or naphthalene ring.

In the present invention, the cyclic group in the cyclic group which mayhave a substituent(s) represented by ring B is preferably a C3-15carbocyclic group or a 3- to 15-membered heterocyclic group, morepreferably a C5-12 monocyclic or bicyclic carbocyclic group or a 5- to12-membered monocyclic or bicyclic heterocyclic group which contain 1 to3 hetero atoms selected from an oxygen atom, a nitrogen atom and asulfur atom and may be partially or fully saturated, and most preferablya benzene, indene, naphthalene, dihydronaphthalene,6,7-dihydro-5H-benzo[7]annulene, pyridine, indole, chromene, benzofuran,benzothiophene, benzoxazole, dihydrobenzoxepine, tetrahydroisoquinoline,isoindoline or tetrahydrobenzazepine ring.

In the present invention, the nitrogen-containing heterocyclic grouprepresented by ring ⁻B¹ is preferably pyrrole, tetrahydropyridine,dihydropyrrole, tetrahydroazepine or the like.

In the present invention, the substituent in the cyclic group which mayhave a substituent(s) represented by ring B is preferably C1-20 alkylwhich may be substituted, C1-20 alkyloxy which may be substituted,carboxy which may be substituted, or a halogen atom, and is morepreferably methyl, ethyl, propyl, isopropyl, tert-butyl, methoxy,carboxy, fluoro, chloro, or trifluoromethyl.

In the present invention, X is preferably a divalent group having 1 to 8atoms in its main chain which is 1 to 4 combinations selected from C1-8alkylene which may be substituted, C2-8 alkenylene which may besubstituted, a nitrogen atom which may be substituted (—NH—), —CO—, —O—,C3-6 cycloalkylene which may be substituted, phenylene which may besubstituted, and the like, and more preferably —CH₂—, —(CH₂)₂—,—(CH₂)₃—, —(CH₂)₄—, —(CH₂)₅—, —(CH₂)₆—, —(CH₂)₇—, —(CH₂)₈—, —CH₂—O—,—(CH₂)₂—O—, —(CH₂)₃—O—, —(CH₂)₄—O—, —(CH₂)₅—O—, —CH═CH—CH₂—O—, or-cyclopropylene-CH₂—O—, which each may be substituted, in which theright side of each group binds to ring B.

In the present invention, Y is preferably a divalent group having 1 to10 atoms in its main chain which is 1 to 4 combinations selected fromC1-10 alkylene which may be substituted, C2-10 alkenylene which may besubstituted, C2-10 alkynylene which may be substituted, a nitrogen atomwhich may be substituted (—NH—), —CO—, —O—, —S—, phenylene which may besubstituted, -(aziridine which may be substituted)-, -(azetidine whichmay be substituted)-, -(pyrrolidine which may be substituted)-,-(piperidine which may be substituted)-, -(piperazine which may besubstituted)-, -(morpholine which may be substituted)-,-(azabicyclo[3.2.1]octane which may be substituted)-,-(azabicyclo[2.2.2]octane which may be substituted)-,-(azabicyclo[2.1.1]hexane which may be substituted)-,-(tetrahydropyridine which may be substituted)-, and the like, and morepreferably —(CH₂)₃—NHCH₂—, —(CH₂)₃—NCH₃—CH₂—, —(CH₂)₃—NH—(CH₂)₂—,—(CH₂)₂—NH—(CH₂)₂—, —(CH₂)₂—CONHCH₂—, —(CH₂)₂—CONH-(m-phenylene)-,—CR^(Y1)═CH—CH₂—NH—(CH₂)₄—, —CR^(Y1)═CH—CH₂—NH—(CH₂)₅—,—CR^(Y1)═CH—CH₂—NH—(CH₂)₂—, —CH═CR^(Y1)—CH₂—NH—(CH₂)₂—,—CR^(Y1)═CH—CH₂—NH—CH₂—, —CH₂-(azetidine)-, —(CH₂)₂-(azetidine)-,—(CH₂)₃-(azetidine)-, —CR^(Y1)═CH—CH₂-(azetidine)-,—CH═CR^(Y1)—CH₂-(azetidine)-, —(CH₂)₃-(piperidine)-,—CR^(Y1)═CH—CH₂-(piperidine)-, in which R^(Y1) represents a hydrogenatom, a halogen atom, or C1-4 alkyl which may be substituted with 1 to 3halogen atoms, and the right side of each group binds to ring B.

In the present invention, Y¹ is preferably a divalent group having 1 to4 atoms in its main chain which is 1 to 4 combinations selected fromC1-3 alkylene which may be substituted and —CO—, and more preferably—CH₂—, —(CH₂)₂—, —(CH₂)₂—CO— or —(CH₂)₃—, which each may be substituted.

In the present invention, Y² is preferably a divalent group having 1 to5 atoms in its main chain which is 1 to 4 combinations selected fromC1-3 alkylene which may be substituted, phenylene which may besubstituted and the like, and is more preferably —CH₂—, —(CH₂)₂— or-(m-phenylene)-, which each may be substituted.

In the present invention, the substituent represented by R¹ ispreferably a halogen atom, C1-20 alkyl which may be substituted, orC1-20 alkyloxy which may be substituted, and more preferably fluoro,chloro, bromo, methyl, trifluoromethyl or methoxy.

In the present invention, R⁷ is preferably a hydrogen atom or C1-20alkyl which may be substituted, and more preferably a hydrogen atom ormethyl.

In the present invention, the nitrogen-containing heterocyclic groupwhich may have a substituent(s) formed by taking one atom in the spacerrepresented by Y¹ together with R⁷ is preferably piperidine,tetrahydropyridine or pyrazine, which each may be substituted, or thelike, and more preferably tetrahydropyridine which may have asubstituent(s).

In the present invention, the nitrogen-containing heterocyclic groupwhich may have a substituent(s) formed by taking one atom in the spacerrepresented by Y² together with R⁷ is azetidine, pyrrolidine,piperidine, or tetrahydropyridine which may be substituted, or the like,and more preferably azetidine which may have a substituent(s).

In the present invention, m is preferably 0, 1 or 2.

In the present invention, n is preferably 0 or 1.

As the compound of the present invention having an ability to bind to anS1P receptor, a compound which is having an ability to bind to EDG-6 andwhich may have an ability to bind to EDG-1 is preferred. It is morepreferable that the action of binding to EDG-1 of the compound is anagonistic activity.

Among the compounds represented by formula (I) in the present invention,preferable compounds are carboxylic acid derivatives represented byformula (IA-1):

wherein all symbols have the same meanings as described above;

formula (IA-2):

wherein all symbols have the same meanings as described above;

formula (IA-3):

wherein all symbols have the same meanings as described above;

formula (IA-4):

wherein all symbols have the same meanings as described above; and

formula (IB):

wherein all symbols have the same meanings as described above;

a prodrug thereof and a salt thereof.

More preferable compounds are carboxylic acid derivatives represented byformula (IA-1-1):

wherein Y¹⁻¹ represents et ylene which may have a substituent(s),propylene which may have a substituent(s) or propenylene which may havea substituent(s); Y²⁻¹ represents ethylene which may have asubstituent(s); and other symbols have the same meanings as describedabove;

formula (IA-1-2):

wherein Y²⁻² represents methylene which may have a substituent(s); andother symbols have the same meanings as described above;

formula (IA-1-3):

wherein Y¹⁻² represents methylene which may have a substituent(s); andother symbols have the same meanings as described above;

formula (IA-2-1):

wherein ring D¹ represents a nitrogen-containing heterocyclic group;Y¹⁻³ represents methylene which may have a substituent(s), ethylenewhich may have a substituent(s), propylene which may have asubstituent(s) or propenylene which may have a substituent(s); R²⁷represents a hydrogen atom or a substituent; t is 0 or an integer of 1to 5; and other symbols have the same meanings as described above;

formula (IA-2-2):

wherein ring D² represents a nitrogen-containing heterocyclic group; andother symbols have the same meanings as described above;

formula (IA-3-1):

wherein ring D³ represents a nitrogen-containing heterocyclic group;Y¹⁻⁴ represents a bond or methylene which may have a substituent(s); andother symbols have the same meanings as described above;

formula (IA-3-2):

wherein ring D⁴ represents a nitrogen-containing heterocyclic group; andother symbols have the same meanings as described above;

formula (IA-3-3):

wherein ring D⁵ represents a nitrogen-containing heterocyclic group; andother symbols have the same meanings as described above;

formula (IB-1-1):

wherein ring B¹⁻¹ represents a nitrogen-containing heterocyclic group;and other symbols have the same meanings as described above;

formula (IB-1-2):

wherein ring B¹⁻² represents a nitrogen-containing heterocyclic group;and other symbols have the same meanings as described above;

formula (I-1):

wherein all symbols have the same meanings as described above;

formula (I-2):

wherein all symbols have the same meanings as described above;

formula (I-S-1):

wherein all symbols have the same meanings as described above;

formula (I-S-2):

wherein all symbols have the same meanings as described above;

formula (I-S-3):

wherein all symbols have the same meanings as described above;

formula (I-S-3a):

wherein all symbols have the same meanings as described above;

formula (I-S-4):

wherein all symbols have the same meanings as described above;

formula (I-S-5):

wherein all symbols have the same meanings as described above;

formula (I-S-6):

wherein all symbols have the same meanings as described above;

formula (I-S-7):

wherein all symbols have the same meanings as described above;

formula (I-S-7a):

wherein all symbols have the same meanings as described above;

formula (I-T):

wherein all symbols have the same meanings as described above; and

formula (I-U):

wherein all symbols have the same meanings as described above;

prodrugs thereof and salts thereof.

In the present invention, R^(S0) is preferably a hydrogen atom, fluoro,chloro, methyl or trifluoromethyl, and more preferably a hydrogen atom,methyl or trifluoromethyl.

The nitrogen containing heterocyclic group represented by ring D¹, ringD³ and ring D⁵ includes, for example, 3- to 9-membered monocyclicheterocyclic aryl and bridged bicyclic heterocyclic group which eachcontains one nitrogen atom, may further contain one or two hetero atomsselected from an oxygen atom, a nitrogen atom and a sulfur atom and maybe partially or fully saturated, and the like. Examples include pyrrole,imidazole, triazole, pyrazole, aziridine, azetidine, pyrroline,pyrrolidine, imidazoline, imidazolidine, triazoline, triazolidine,pyrazoline, pyrazolidine, dihydropyridine, tetrahydropyridine,piperidine, dihydropyrazine, tetrahydropyrazine, piperazine,dihydropyrimidine, tetrahydropyrimidine, perhydropyrimidine,dihydropyridazine, tetrahydropyridazine, perhydropyridazine,dihydroazepine, tetrahydroazepine, perhydroazepine, dihydrodiazepine,tetrahydrodiazepine, perhydrodiazepine, dihydrooxazole,tetrahydrooxazole (oxazolidine), dihydroisoxazole, tetrahydroisoxazole(isoxazolidine), dihydrothiazole, tetrahydrothiazole (thiazolidine),dihydroisothiazole, tetrahydroisothiazole (isothiazolidine),dihydrofurazane, tetrahydrofurazane, dihydrooxadiazole,tetrahydrooxadiazole (oxadiazolidine), dihydrooxazine,tetrahydrooxazine, dihydrooxazepine, tetrahydrooxazepine,perhydrooxazepine, dihydrooxadiazepine, tetrahydrooxadiazepine,perhydrooxadiazepine, dihydrothiadiazole, tetrahydrothiadiazole(thiadiazolidine), dihydrothiazine, tetrahydrothiazine,dihydrothiadiazine, tetrahydrothiadiazine, dihydrothiazepine,tetrahydrothiazepine, perhydrothiazepine, dihydrothiadiazepine,tetrahydrothiadiazepine, perhydrothiadiazepine, morpholine,thiomorpholine, oxathiane, azabicyclo[2.2.1]heptane,azabicyclo[3.1.1]heptane, azabicyclo[3.2.1]octane(8-azabicyclo[3.2.1]octane, etc.), azabicyclo[2.2.2]octane(2-azabicyclo[2.2.2]octane, etc.), diazabicyclo[2.2.2]octane,azabicyclo[2.1.1]hexane (5-azabicyclo[2.1.1]hexane, etc.), and the like.

The nitrogen containing heterocyclic group represented by ring D² andring D⁴ includes, for example, 4- to 9-membered monocyclic aryl andbridged heterocyclic group which each contains one nitrogen atom, mayfurther contain one to two hetero atoms selected from an oxygen atom, anitrogen atom and a sulfur atom and which may be partially or fullysaturated. Examples include pyrrole, pyrazole, azetidine, pyrroline,pyrrolidine, pyrazoline, pyrazolidine, dihydropyridine,tetrahydropyridine, piperidine, dihydropyrimidine, tetrahydropyrimidine,perhydropyrimidine, dihydropyridazine, tetrahydropyridazine,perhydropyridazine, dihydroazepine, tetrahydroazepine, perhydroazepine,dihydrodiazepine, tetrahydrodiazepine, perhydrodiazepine,dihydroisoxazole, tetrahydroisoxazole (isoxazolidine),dihydroisothiazole, tetrahydroisothiazole (isothiazolidine),dihydrooxazine, tetrahydrooxazine, dihydrooxazepine,tetrahydrooxazepine, perhydrooxazepine, dihydrooxadiazepine,tetrahydrooxadiazepine, perhydrooxadiazepine, dihydrothiazine,tetrahydrothiazine, dihydrothiazepine, tetrahydrothiazepine,perhydrothiazepine, dihydrothiadiazepine, tetrahydrothiadiazepine,perhydrothiadiazepine, azabicyclo[2.2.1]heptane,azabicyclo[3.1.1]heptane, azabicyclo[3.2.1]octane(8-azabicyclo[3.2.1]octane, etc.), azabicyclo[2.2.2]octane(2-azabicyclo[2.2.2]octane, etc.), diazabicyclo[2.2.2]octane,azabicyclo[2.1.1]hexane (5-azabicyclo[2.1.1]hexane), and the like.

The nitrogen-containing heterocyclic group represented by ring B¹⁻¹includes, for example, 4- to 9-membered monocyclic heterocyclic arylwhich contains one nitrogen atom, may further contain one or two heteroatoms selected from an oxygen atom, a nitrogen atom and a sulfur atomand may be partially or fully saturated, and the like. Examples includepyrrole, imidazole, triazole, pyrazole, azetidine, pyrroline,pyrrolidine, imidazoline, imidazolidine, triazoline, triazolidine,pyrazoline, pyrazolidine, dihydropyridine, tetrahydropyridine,piperidine, dihydropyrazine, tetrahydropyrazine, piperazine,dihydropyrimidine, tetrahydropyrimidine, perhydropyrimidine,dihydropyridazine, tetrahydropyridazine, perhydropyridazine,dihydroazepine, tetrahydroazepine, perhydroazepine, dihydrodiazepine,tetrahydrodiazepine, perhydrodiazepine, dihydrooxazole,tetrahydrooxazole (oxazolidine), dihydroisoxazole, tetrahydroisoxazole(isoxazolidine), dihydrothiazole, tetrahydrothiazole (thiazolidine),dihydroisothiazole, tetrahydroisothiazole (isothiazolidine),dihydrofurazane, tetrahydrofurazane, dihydrooxazine, tetrahydrooxazine,tetrahydrooxadiazine, dihydrooxazepine, tetrahydrooxazepine,perhydrooxazepine, dihydrooxadiazepine, tetrahydrooxadiazepine,perhydrooxadiazepine, dihydrothiazine, tetrahydrothiazine,tetrahydrothiadiazine, dihydrothiazepine, tetrahydrothiazepine,perhydrothiazepine, dihydrothiadiazepine, tetrahydrothiadiazepine,perhydrothiadiazepine, morpholine, thiomorpholine, and the like.

The nitrogen-containing heterocyclic group represented by ring B¹⁻²includes, for example, 5- to 9-membered monocyclic heterocyclic arylwhich contains one nitrogen atom, may further contain one or two heteroatoms selected from an oxygen atom, a nitrogen atom and a sulfur atomand may be partially or fully saturated, and the like. Examples includepyrrole, pyrazole, pyrroline, pyrrolidine, imidazoline, imidazolidine,triazolidine, pyrazoline, pyrazolidine, dihydropyridine,tetrahydropyridine, piperidine, dihydropyrazine, tetrahydropyrazine,piperazine, dihydropyrimidine, tetrahydropyrimidine, perhydropyrimidine,dihydropyridazine, tetrahydropyridazine, perhydropyridazine,dihydroazepine, tetrahydroazepine, perhydroazepine, dihydrodiazepine,tetrahydrodiazepine, perhydrodiazepine, dihydrooxazole,tetrahydrooxazole (oxazolidine), dihydroisoxazole, tetrahydroisoxazole(isoxazolidine), dihydrothiazole, tetrahydrothiazole (thiazolidine),dihydroisothiazole, tetrahydroisothiazole (isothiazolidine),dihydrooxazine, tetrahydrooxazine, dihydrooxazepine,tetrahydrooxazepine, perhydrooxazepine, dihydrooxadiazepine,tetrahydrooxadiazepine, perhydrooxadiazepine, dihydrothiazine,tetrahydrothiazine, tetrahydrothiadiazine, dihydrothiazepine,tetrahydrothiazepine, perhydrothiazepine, dihydrothiadiazepine,tetrahydrothiadiazepine, perhydrothiadiazepine, morpholine,thiomorpholine, and the like.

Specific examples of

in formula (IA-2-1) include

and the like.

Specific examples of

in formula (IA-2-2) include

and the like.

Specific examples of

in formula (IA-3-1) include

and the like.

Specific examples of

in formula (IA-3-2) include

and the like.

Specific examples of

in formula (IA-3-3) include

and the like.

Specific examples of

in formula (IB-1-1) include

and the like.

Specific examples of

in formula (IB-1-2) include

and the like.

In a compound represented by formula (Ia) for producing a pharmaceuticalcomposition, R^(1a) is preferably C1-8 alkyl, C1-8 alkoxy or a halogenatom, more preferably methyl, methoxy, chloro or fluoro; ring A^(a) ispreferably a C5-7 monocyclic carbocyclic group, more preferably abenzene ring; E^(a) is preferably —O—, —S— or —NR^(6a)—, and morepreferably —O—; R^(2a) is preferably C1-8 alkyl, C1-8 alkoxy or ahalogen atom, and more preferably methyl, methoxy, chloro or fluoro;R^(3a) is preferably a hydrogen atom, C1-4 alkyl or a halogen atom, andmore preferably a hydrogen atom, methyl or chloro; R^(4a) is preferablya hydrogen atom; the group formed by taking R^(2a) together with R^(4a)is preferably —CH₂CH₂—; G^(a) is preferably —CONR^(7a)—, NR^(7a)CO—,—NR^(7a)SO₂—, —CH₂NR^(7a)— or —NR^(7a)CH₂, and more preferably—CONR^(7a)—, —CH₂NR^(7a)— or —NR^(7a)CH₂; R^(7a) is preferably ahydrogen atom or C1-8 alkyl, and more preferably a hydrogen atom ormethyl; Q^(a) is preferably C1-4 alkylene or

wherein all symbols have the same meanings as described above,

and more preferably methylene, ethylene or phenylene; J¹, J, J³ and J⁴each is preferably a carbon atom or a nitrogen atom, and more preferablya carbon atom; R^(5a) is preferably a halogen atom or —COOR^(11a), andmore preferably chloro or —COOH; p is preferably 0, 1 or 2, and morepreferably 0 or 1; q is preferably 4, 5 or 6; r is preferably 0 or 1;and s is preferably 0 or 1.

In the present invention, all of the compounds of formula (I) containingcombinations of the preferable groups and the preferable rings as citedabove are preferred. In particular, more preferred compounds are thosedescribed in Examples and2-[3-(4-(5-phenylpentyloxy)phenyl)propanoylamino]acetic acid,3-[3-(4-(5-phenylpentyloxy)phenyl)propylamino]propanoic acid,3-[2-(4-(5-phenylpentyloxy)phenyl)ethylamino]propanoic acid,2-[3-(4-(5-phenylpentyloxy)phenyl)propylamino]acetic acid,2-[N-methyl-3-(4-(5-phenylpentyloxy)phenyl)propylamino]acetic acid,3-carboxy-5-[3-(4-(5-phenylpentyloxy)phenyl)propanoylamino]benzoic acidor2-chloro-5-[3-(2-fluoro-4-(5-phenylpentyloxy)phenyl)propanoylamino]benzoicacid, N-{(2E)-3-[4-(3-phenylpropoxy)phenyl]prop-2-enyl}-β-alanine,N-{[6-(3-phenylpropoxy)-2-naphthyl]methyl}-β-alanine,1-{[6-(3-phenylpropoxy)-2-naphthyl]methyl}azetidine-3-carboxylic acid,1-{[6-(3-phenylpropoxy)-2-naphthyl]methyl}piperidine-4-carboxylic acid,N-{(2E)-3-[2-methyl-4-(3-phenylpropoxy)phenyl]prop-2-enyl}-β-alanine,1-{(2E)-3-[4-(3-phenylpropoxy)phenyl]-2-propenyl}piperidine-4-carboxylicacid,1-({(2E)-3-[4-(3-phenylpropoxy)phenyl]-2-propenyl}azetidine-3-carboxylicacid, N-{3-[4-(3-phenylpropoxy)phenyl]propyl}-β-alanine,N-((2E)-3-{2-methyl-4-[(5-phenylpentyl)oxy]phenyl}prop-2-enyl)-β-alanine,N-((2E)-3-{4-[(5-phenylpentyl)oxy]phenyl}-2-propenyl)-alanine, a prodrugthereof or a salt thereof,

More specific embodiments include the following compounds, saltsthereof, solvates thereof and prodrugs thereof, compounds described inExamples and the like.

-   (1) 4-{3-[4-(4-phenylbutoxy)phenyl]propyl}morpholine-2-carboxylic    acid,-   (2)    4-((2E)-3-{4-[4-(4-chlorophenyl)butyl]-2-methylphenyl}-2-propenyl)-1-methylpiperazine-2-carboxylic    acid,-   (3)    5-oxo-1-{[6-(5-phenylpentanoyl)-2-naphthyl]methyl}pyrrolidine-3-carboxylic    acid,-   (4)    1-(3-{2-methyl-4-[(5-phenylpentyl)oxy]phenyl}-3-oxopropyl)piperidine-4-carboxylic    acid,-   (5)    4-hydroxy-1-(2-({6-[(4-isobutylbenzyl)oxy]-1-naphthyl}ethyl)piperidine-4-carboxylic    acid,-   (6)    1-(2-{5-[3-(2,4-dichlorophenyl)propoxy]-1H-indol-1-yl}ethyl)azetidine-3-carboxylic    acid,-   (7)    1-((2E)-3-{4-[(5-phenylpentyl)oxy]phenyl}-2-propenyl)aziridine-2-carboxylic    acid,-   (8)    N-({6-[4-(3-chlorophenyl)butoxy]-2-naphthyl}methyl)-N-(2-hydroxyethyl)-β-alanine,-   (9)    5-{(2E)-3-[2-methyl-4-(4-phenylbutoxy)phenyl]-2-propenyl}-5-azabicyclo[2.1.1]hexane-6-carboxylic    acid,-   (10)    8-{[6-(4-phenylbutoxy)-3,4-dihydronaphthalen-2-yl]methyl}-8-azabicyclo[3.2.1]octane-3-carboxylic    acid,-   (11)    1-({7-[4-(4-chlorophenyl)butyl]-4-oxo-4H-chromen-3-yl}methyl)pyrrolidine-3-carboxylic    acid,-   (12)    N-{[6-(3-phenylpropoxy)-3,4-dihydronaphthalen-2-yl]methyl}-β-alanine,-   (13)    1-({2-[4-(2-chlorophenyl)butyl]-1-benzothien-5-yl}methyl)azetidine-3-carboxylic    acid,-   (14)    1-({2-[4-(2-naphthyl)butyl]-1,3-benzoxazol-5-yl}methyl)piperidine-4-carboxylic    acid,-   (15)    N-(2-hydroxyethyl)-N-({5-[(7E)-8-phenyl-7-octenoyl]pyridin-2-yl}methyl)-β-alanine,-   (16)    N-({3-[3-(2,4-dimethylphenyl)propoxy]-6,7-dihydro-5H-benzo[7]annulen-8-yl}methyl)-β-alanine,-   (17)    1-{[8-(4-phenylbutoxy)-2,3-dihydro-1-benzoxepin-4-yl]methyl}pyrrolidine-3-carboxylic    acid,-   (18)    1-({2-[(3-isobutylbenzyl)oxy]-5-oxo-5H-benzo[7]annulen-6-yl}methyl)azetidine-3-carboxylic    acid,-   (19) N-[(5-nonyl-1-benzothien-2-yl)methyl]-β-alanine,-   (20) 3-{4-[4-(3-phenylpropoxy)phenyl]piperidin-1-yl}propanoic acid,-   (21)    3-[5-[4-(3-cyclohexylpropoxy)benzyl]-3,6-dihydropyridin-1(2H)-yl]propanoic    acid,-   (22)    3-[5-{3-[(6-phenylhexyl)oxy]phenyl}-3,6-dihydropyridin-1(2H)-yl]propanoic    acid,-   (23)    3-{4-[3-({5-[4-(trifluoromethyl)phenyl]pentyl}oxy)phenyl]-2-azabicyclo[2.2.2]-2-octyl}propanoic    acid,-   (24)    3-(4-{3-[3-(3-isobutylphenyl)propoxy]phenyl}-2-azabicyclo[2.2.2]-2-octyl)propanoic    acid,-   (25)    3-[3-(3-{2-[3-(2-phenylethoxy)phenyl]ethoxy}phenyl)piperidin-1-yl]propanoic    acid,-   (26) 3-{4-[3-(octyloxy)phenyl]piperidin-1-yl}propanoic acid,-   (27)    3-(3-{6-[2-(2-chloro-6-methylphenyl)ethoxy]-2-naphthyl}pyrrolidin-1-yl)propanoic    acid,-   (28) 3-(2-{4-[(5-phenylpentyl)oxy]phenyl}azetidin-1-yl)propanoic    acid,-   (29) 3-(3-{(3-[(5-methylhexyl)oxy]phenyl}azetidin-1-yl)propanoic    acid,-   (30)    3-methyl-3-[6-{3-[4-(trifluoromethyl)phenyl]propoxy}-3,4-dihydroisoquinolin-2(1H)-yl]butanoic    acid,-   (31)    3-(5-chloro-6-{3-[4-chloro-2-(trifluoromethyl)phenyl]propoxy}-1,3-dihydro-2H-isoindol-2-yl)propanoic    acid,-   (32)    3-[6-methoxy-5-(octyloxy)-1-oxo-1,3-dihydro-2H-isoindol-2-yl]propanoic    acid,-   (33)    3-[7-(3-cyclohexylpropoxy)-1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl]propanoic    acid,-   (34)    3-{7-[2-(1,1′-biphenyl-3-yl)ethyl]-8-chloro-1,2,4,5-tetrahydro-3H-3-benzazepin-3-yl}propanoic    acid.

Isomers:

Unless otherwise specifically mentioned, all isomers are included in thepresent invention. For example, alkyl, alkenyl, alkynyl, alkyloxy,alkoxy, alkenyloxy, alkynyloxy, alkylthio, alkylsulfinyl, alkylsulfonyl,alkylene, alkenylene, alkynylene, acyl and acyloxy include straightchain and branched ones. Moreover, all of isomers due to double bond,ring and fused ring (E-, Z-, cis- and trans-forms), isomers due topresence of asymmetric carbon(s) etc. (R-, S-, α- and β-configuration,enantiomer and diastereomer), optically active compounds having opticalrotation (D-, L-, d- and l-forms), polar compound by chromatographicseparation (more polar compound and less polar compound), equilibriumcompounds, rotational isomers, a mixture thereof in any proportion and aracemic mixture are included in the present invention.

In the present invention, unless otherwise-specified, the symbol

means that the α-configuration substituent, the symbol

means that the β-configuration substituent, the symbol

means α-configuration, β-configuration or a mixture of α-configurationand β-configuration by an appropriate ratio, and the symbol

means a mixture of α-configuration and β-configuration by an appropriateratio as would be clear to the person skilled in the art.

Salt and Solvate:

The compound of the present invention can be converted into a salt byknown methods. The salt is preferably a non-toxic and water-solublesalt.

The salt of the present invention includes, for example, salts of alkalimetal (such as potassium, sodium and lithium), salts of alkaline earthmetal (such as calcium and magnesium), ammonium salts (such astetramethylammonium salt and tetrabutylammonium salt), salts of organicamine (such as triethylamine, methylamine, dimethylamine,cyclopentylamine, benzylamine, phenethylamine, piperidine,monoethanolamine, diethanolamine, tris(hydroxymethyl)methylamine,lysine, arginine and N-methyl-D-glucamine) and acid addition salts [suchas inorganic acid salts (e.g., hydrochloride, hydrobromide, hydroiodide,sulfate, phosphate and nitrate) and organic acid salts (e.g., acetate,trifluoroacetate, lactate, tartrate, oxalate, fumarate, maleate,benzoate, citrate, methanesulfonate, ethanesulfonate, benzenesulfonate,toluenesulfonate, isethionate, glucuronate and gluconate), etc.].

The compound of the present invention or a salt thereof can be convertedinto a solvate by known methods. The solvate is preferably a non-toxicand water-soluble solvate.

The solvate of the present invention includes, for example, solvates ofwater, alcohols (e.g., methanol, ethanol, etc.), and the like.

Prodrugs:

A prodrug of the compound represented by formula (I) means a compoundwhich is converted to the compound represented by formula (I) byreaction with an enzyme, gastric acid or the like in the living body.For example, with regard to a prodrug of the compound represented byformula (I), when the compound represented by formula (I) has an aminogroup, compounds in which the amino group is, for example, acylated,alkylated or phosphorylated (e.g., compounds in which the amino group ofthe compound represented by formula (I) is eicosanoylated, alanylated,pentylaminocarbonylated,(5-methyl-2-oxo-1,3-dioxolen-4-yl)methoxycarbonylated,tetrahydrofuranylated, pyrrolidylmethylated, pivaloyloxymethylated,acetoxymethylated, tert-butylated, etc.); when the compound representedby formula (I) has a hydroxy group, compounds where the hydroxy groupis, for example, acylated, alkylated, phosphorylated or borated (e.g.,compounds in which the hydroxy group of the compound represented byformula (I) is acetylated, palmitoylated, propanoylated, pivaloylated,succinylated, fumarylated, alanylated ordimethylaminomethylcarbonylated); and when the compound represented byformula (I) has a carboxy group, compounds where the carboxy group ofthe compound represented by formula (I) is, for example, esterified oramidated (e.g., compounds in which the carboxy group of the compoundrepresented by formula (I) is made into ethyl ester, phenyl ester,carboxymethyl ester, dimethylaminomethyl ester, pivaloyloxymethyl ester,ethoxycarbonyloxyethyl ester, phthalidyl ester,(5-methyl-2-oxo-1,3-dioxolen-4-yl)methyl ester,cyclohexyloxycarbonylethyl ester or methylamide). Those compounds may beprepared by a known method per se. The prodrug of the compoundrepresented by formula (I) may be either a hydrate or a non-hydrate. Aprodrug of the compound represented by formula (I) may also be acompound which is converted to the compound represented by formula (I)under physiologic condition as described in “Iyakuhin no kaihatsu, Vol.7 (Bunshi-sekkei), pp. 163-198 (Hirokawa-Shoten), 1990”. Also, thecompound represented by formula (I) may also be labeled by a radioisotope (such as ³H, ¹⁴C, ³⁵S, ¹²⁵I, etc).

Examples of the prodrug of the compound represented by formula (I) inthe present invention include a compound represented by the followingformula (I-A):

wherein R²⁴ represents C1-8 alkyl or C1-8 alkyl substituted with one ortwo of hydroxy or amino; and other symbols have the same meanings asdescribed above;

a compound represented by the following formula (I-B):

wherein R²⁵ and R²⁶ each independently represents a hydrogen atom, C1-8alkyl or C1-8 alkyl substituted with one or two of hydroxy or amino; andother symbols have the same meanings as described above; and

a compound represented by the following formula (I-C):

wherein all symbols have the same meanings as described above.

The compounds represented by formula (I) in the present invention areexcellent in solubility and absorbability, exhibit a prolonged action(ability to bind to an S1P receptor (in particular, EDG-6, preferablyEDG-1 and EDG-6)), are little affected by drug-metabolic enzymes andhave low toxicity. These characteristics are the most importantphysical, chemical and pharmaceutical characteristics required indeveloping drugs. Because of fulfilling these requirements, therefore,the compounds represented by formula (I) in the present invention arelikely usable as highly excellent drugs (see The Merck Manual ofDiagnosis and Therapy, 17th Ed., Merck & Co.).

It can be assessed that the compound represented by formula (I) in thepresent invention is useful as a drug by various experimental methodsdescribed below, methods described in Biological Examples, and theirmethods which properly improved. It can be also easily assessed that thecompound of the present invention has a good pharmacokinetic propertysuch as a length of serum half-life, a stability in the gastrointestinaltract, an absorption of oral preparations, bioavailability, etc. byknown methods, for example, a method described in Yakubutsubioavailability (Hyouka to kaizen no kagaku), Jul. 6, 1998,Gendaiiryou-sha, etc.

(I) Experiments for Evaluating the Properties of Compound Evaluation ofthe Solubility of the Present Invention Compound Method:

About 3 to 5 mg of a test compound having been heated to 37° C.(measured with a thermometer in practice) is sampled into a test tube.Then, a solvent (Official Solution I as specified in The JapanesePharmacopoeia, Official Solution II as specified in The JapanesePharmacopoeia and Official Solution II added by bovine bile acid inartificial bile juice (0.5% (w/w), SIGMA)), a pH 7.4 buffer solution(prepared by diluting 4-fold McIlvaine buffer), a pH 4.0 buffer solution(prepared by diluting 4-fold McIlvaine buffer), purified water andsaline, having been heated to 37° C. in a water bath, are added theretoto respectively give concentrations of 1.5 mg/mL. After stirring at aconstant temperature of 37° C. for 30 minutes, the mixture is filteredthrough a filter (in general, DISMIC-13cp, cellulose acetate,hydrophilic, 0.20 μm, Advantec). Immediately thereafter, the filtrate isdiluted 2-fold with an organic solvent in which the test compound ishighly soluble (acetonitrile or methanol) and stirred. The solubility ofthe test compound can be evaluated by concentrating its concentration bythe external standard method with the use of HPLC.

Absorption Test of the Present Invention Compound in Oral Administrationto Dog Method:

To fasted adult beagle dogs, pentagastrin (10 μg/kg) is intramuscularly(i.m.) injected. Fifteen minutes thereafter, each test compound isorally administered (100 mg/body) with water (20 mL). Fifteen minutesthereafter, pentagastrin (10 μg/kg) is intramuscularly (i.m.) injected.Next, 15 and 30 minutes and 1, 2, 3, 4, 6, 8 and 10 hours after theadministration of the test compound, the blood of the animal iscollected and extracted with acetonitrile. Then, the concentration ofthe compound in the plasma is measured by high-performance liquidchromatography (the internal standard method). By using theconcentrations of the blood in the plasma thus obtained, it is possibleto determine the area under the plasma concentration curve (AUC, μgmin/mL) and the maximum concentration in the plasma (C_(max), ng/mL).

(II) Experiments for Evaluating the Efficacy of the Present InventionCompound (Measurement of Cytokines)

The effects of the present invention compounds on cytokine productioncan be confirmed by the following experiments. For example, the effectsof the present invention compounds can be evaluated in cytokineproduction systems with the use of THP-1 (a human monocyte cell line),diluted whole human blood, mouse or rat. An example of the experimentfor evaluating the effect of inhibiting the production of TNF-α, whichis one of cytokine's, will be illustrated.

Effect of Inhibiting TNF-α Production Using Human Cell Line Method:

To a 96-well plate for cell incubation, 50 μL portions oflipopolysaccharide (LPS; Difco #3120-25-0) adjusted to 40 ng/mL by usingRPMI-1640 medium containing 10% of fetal bovine serum (hereinafterreferred to as RPMI-1640) and RPMI-1640 containing a test compound areadded. Further, 100 μL of a THP-1 (DAINIPPON PHARMA #06-202) cellsuspension adjusted to 2×10⁶ cells/mL by using RPMI-1640 is added,followed by incubation for 90 minutes at 37° C. (5% CO₂, 95% air). Afterthe completion of the reaction, the culture supernatant is collected andthe amount of the TNF-α thus produced is measured by using an ELISA kit(Invitrogen #850090192).

The activity of inhibiting the TNF-α production can be calculated as aninhibition ratio (%) in accordance with the following formula.

Inhibition ratio(%)={(A _(C) −A _(X))/(A _(C) −A _(B))}×100

A_(B): value measured without LPS-elicitation.A_(C): value measured under LPS-elicitation in the absence of testcompound.A_(X): value measured under LPS-elicitation in the presence of testcompound.

The inhibition ratios of the compound are measured at variousconcentrations. Thus, the concentration at which the compound shows aninhibition ratio of 50% (IC₅₀) can be determined from the inhibitioncurve.

Effect of Inhibiting TNF-α Production Using Diluted Whole Human BloodMethod:

Human peripheral blood is obtained by collecting the heparinized bloodof a male healthy volunteer. The peripheral blood thus collected isfinally diluted 10-fold with RPM1640 medium (manufactured by Gibco BRL)before using.

To a 96-well plate for cell incubation, a lipopolysaccharide (LPS)solution (final concentration 100 ng/ml) (Bacto W. E. coli 055:B5;manufactured by DIFCO Lab.), a solution of a test compound and dilutedwhole blood are added. After incubating the mixture at 37° C. for 6hours, the 96-well plate is centrifuged and the supernatant iscollected. Then, the amount of the TNF-α thus produced in thesupernatant is measured by using an ELISA kit (manufactured by R&Dsystem). By referring the difference in the TNF-α level between anuntreated group and the LPS-elicitation group as to 100%, the inhibitionratio (%) of the test compound is determined and the 50% inhibitionconcentration (IC₅₀) is calculated.

Effect of Inhibiting TNF-α Production in Mice (IntravenousAdministration) Method:

The activity of inhibiting TNF-α production can be measured by a methodreported in a document (ed. by Kazuo Ouchi, Seibutsu Kagaku Jikken Koza12, 707 (1994), Hirokawa Shoten, Tokyo) with an appropriatemodification. For example, a test compound is intravenously administeredat various concentrations to female mice (BALB/c, 7-week-old) and thenLPS (100 μg/mouse) (Bacto W. E. coli 055:B5; manufactured by DIFCO Lab.)is intraperitoneally administered. Ninety minutes after the LPSadministration, heparinized blood is collected from the aortaabdominalis under ether anesthesia. Then, the plasma is immediatelyprepared and stored at −80° C. The TNF-α content in the plasma isdetermined by using a mouse cytokine ELISA kit (manufactured byGenzyme). By referring the difference in the TNF-α content in the plasmabetween an untreated group and the LPS-elicitation group as to 100%, theinhibition ratio (%) of the test compound is determined and the 50%inhibition concentration (IC₅₀) is calculated.

Effect of Inhibiting TNF-α Production in Mice (Oral Administration)Method:

A test compound suspended in a vehicle is orally administered to mice(male C57BL/6). Half an hour thereafter, lipopolysaccharide (LPS,055:B5, Sigma) is intraperitoneally administered in a dose of 60 mg/kg.To a control group, vehicle is orally administered. Sixty minutes afterthe LPS treatment, heparinized blood is collected from the aortaabdominalis under ether anesthesia. Then, the blood is centrifuged(12000 r.p.m.) at 4° C. for 3 minutes to give the plasma. The obtainedplasma samples are stored at −80° C. before using. The TNF-α content inthe plasma is determined by using an ELISA kit (R&D systems).

Effect of Inhibiting TNF-α Production in Rats (Oral Administration)Method:

A test compound contained in a vehicle is orally administered to femaleLew rats (CHARLES RIVER LABORATORIES, JAPAN). Two hours thereafter,lipopolysaccharide (LPS, 055:B6, Difco) is intravenously administered ina dose of 10 μg/kg (each group having 5 animals). To a control group,vehicle is orally administered (5 animals). Ninety minutes after the LPStreatment, heparinized blood is collected from the aorta abdominalisunder ether anesthesia. Then, the blood is centrifuged (12,000 r.p.m., 3min, 4° C.) to give the plasma. The obtained plasma samples are storedat −80° C. before using. The TNF-α content in the plasma is determinedby using an ELISA kit (Genzyme/Techne, #10516).

The activity of inhibiting the TNF-α production can be calculated as aninhibition ratio (%) in accordance with the following formula.

Inhibition ratio(%)={(A _(C) −A _(X))/A _(C)}×100

A_(B): value measured under LPS-elicitation without the administrationof test compound.A_(C): value measured under LPS-elicitation with the administration oftest compound.

In the case of using another cytokine as a substitute for TNF-α, theeffects of the present invention compounds on the cytokine productioncan be evaluated by appropriately modifying the methods as describedabove. For example, assay can be made by incubating a commerciallyavailable ELISA kit for another cytokine (for example, a Th1 type or Th2type cytokine such as IL-1, IL-2, IL-4, IL-5, IL-6, IL-8, IL-12, TGF-β,interferon γ, etc.) as a substitute for the ELISA kits for TNF-α for aperiod of time suitable for each cytokine and using a substance capableof inducing each cytokine (for example, phorbol-12-myristate-13-acetate(PMA), concanavalin A (ConA), etc.).

(III) Experiments for Evaluating the Efficacy of the Present InventionCompound (Animal Model of Diseases)

It can be confirmed by using the following experiments that the presentinvention compounds have preventive and/or therapeutic effects onallergic diseases. For example, the preventive and/or therapeuticeffects on atopic dermatitis or allergic rhinitis can be confirmed bythe following experiments.

Mouse Delayed Dermatitis Model Method:

The abdominal hair of 14-week-old male BALB/cAnCrj mice (CHARLES RIVERLABORATORIES, JAPAN) is shaven. On the next day, 0.1 mL of a 7% solutionof picryl chloride (PC, Tokyo Kasei Kogyo, cat. C0307) in ethanol isapplied to the whole shaven part with a pippette to thereby sensitizethe animal. Four days thereafter, 0.02 mL/ear of a 2% PC solution inolive oil is applied to the front and back faces of both ear auricles byusing a pippette and thus mouse delayed dermatitis is elicited. Twentyhours thereafter, the thicknesses of both ear auricles are measured withDial Thickness Gauge (Ozaki Seisakusho) and the mean is calculated tothereby evaluate edema in the ear auricles. A test compound is suspendedin a 0.5% methylcellulose solution 30 minutes before the elicitation andthen orally administered once or administered as an application agent.

As the hapten, it is also possible to use4-ethoxymethylene-2-phenyl-2-oxazolin-5-one; oxalone) or the like as asubstitute for picryl chloride.

Mouse DTH Model Method:

The abdominal hair of mice (male BALB/c) is shaven with clippers and a7% (w/v) solution of 2,4,6-trinitrochlorobenzene (TNCB) in ethanol (100μl) is applied to the abdomen to thereby sensitize the animals. Sevendays after the sensitization, a 1% (w/v) TNCB solution in olive oil isapplied to an ear auricle (right, both faces) of the mouse forelicitation. A test compound is dissolved in a vehicle and then orallyadministered or applied to both faces of the right ear (20 μL) beforethe application of TNCB. To the control group, the vehicle is applied.Immediately before the administration of the test compound and 24 hoursafter the TNCB application, the thickness of the mouse ear auricle ismeasured with Dial Thickness Gauge (Ozaki Seisakusho) as an indicationof the efficacy to the mouse DTH model.

As the hapten, it is also possible to use4-ethoxymethylene-2-phenyl-2-oxazolin-5-one; oxalone) or the like as asubstitute for TNCB.

Mouse Model of Dermatitis Caused by Continuous Application of HaptenMethod:

A 1% (w/v) TNCB solution (acetone:olive oil=4:1) is applied (20 μl) toan ear auricle (right, both faces) of mice (male Balb/c) to perform theprimary sensitization. Seven days after the sensitization, a 1% (w/v)TNCB solution (acetone:olive oil=4:1) is applied (20 μl) for elicitation(day 0). The same procedure as the day 0 is repeated on the days 2, 4,6, 8, 10, 12, 14 and 16. A test compound is dissolved in a vehicle andthen orally administered or applied to both faces of the right ear (20μL) before the application of TNCB. To the control group, the vehicle isapplied. Immediately before the administration of the test compound and24 hours after the TNCB application, the thickness of the mouse earauricle is measured with Dial Thickness Gauge (Ozaki Seisakusho) as anindication of the efficacy to the mouse model of dermatitis induced bythe continuous application of hapten.

As the hapten, it is also possible to use4-ethoxymethylene-2-phenyl-2-oxazolin-5-one; oxalone) or the like as asubstitute for TNCB.

Inhibitory Effect of Invention Compound on Spontaneous ScratchingBehavior of NC Mouse with Spontaneous Onset of Dermatitis

Method:

Male NC mice suffering from the spontaneous onset of dermatitis areemployed. The mice are put into a monitoring cage and allow toacclimatize to the environment for 30 minutes. Then, scratchingbehaviors within an hour are videotaped in an unmanned room. Byreplaying the video, a series of movements of scratching the face, ears,back neck and around these parts with hinder legs are regarded as asingle scratching behavior and these behaviors are counted. A testcompound or a control (0.5% aqueous solution of methylcellulose) isorally administered 3 to 5 times in total at intervals of 30 minutes.Immediately after the second administration, the scratching behaviorsare videotaped and counted for 1 to 3 hours, thereby making evaluation.

Inhibitory Effect on Spontaneous Scratching Behavior of BN Rat withDNFB-Induced Dermatitis

Firstly, 0.3% dinitrofluorobenzene (DNFB) is repeatedly applied to thescalp of Brown Norway (BN) rats to elicit dermatitis. Then, an increasein scratching behaviors is observed 24 to 27 hours after theapplication. The effect of the present invention compound on thescratching behaviors can be evaluated.

Method:

To the shaven scalp of male BN rats, 0.3% DNFB dissolved in a mixedsolvent of acetone and olive oil is applied as a hapten. To anon-elicitation group, the mixed solvent of acetone and olive oil isapplied. One week thereafter, these substances are applied to the scalpagain and the application procedures are repeated thrice every otherday. Then, 24 to 27 hours after the fourth application, the rats arevideotaped in an unmanned room. By replaying the video, a series ofmovements of scratching around the hapten-application site with hinderlegs are regarded as a single scratching behavior and these behaviorsare counted. A test compound or a control (0.5% aqueous solution ofmethylcellulose) is orally administered 12 to 48 hours after the thirdto sixth administrations. To a non-elicited group, 0.5% aqueous solutionof methylcellulose is orally administered. From 30 minutes after theadministration, the scratching behaviors are videotaped for 3 hours andcounted, thereby making evaluation.

Allergic Rhinitis Model Method:

To male Crj Hartley guinea pigs (6-week-old), ovalbumin is administeredin the procedure as shown in Table 1 to thereby construct an allergicrhinitis model.

TABLE 1 Day Dose Administration route 0 0.5 mg/0.5 mL Intraperitoneal 21.0 mg/0.5 mL Intraperitoneal 22 0.1% 40 μL Nasal (both sides) 24 0.2%40 μL Nasal (both sides) 27 0.4% 40 μL Nasal (both sides) 31 0.5% 40 μLNasal (both sides) 36 1.0% 40 μL Nasal (both sides) 41 1.0% 40 μL Nasal(both sides)

After the initiation for 42 days, a tube is inserted into the airway ofeach guinea pig under anesthesia and maintained at a constanttemperature by a heat pat. Then, 40 μL of a test compound or saline isdropped into the both nasal cavities. Ten minutes thereafter, 40 μL of1% ovalbumin is dropped into the both nasal cavities. Thirty minutesafter the dropping of ovalbumin, the moisture in the nose is eliminatedwith absorbent cotton. Fifteen minutes thereafter, the absorbent cottonhaving been weighed is inserted into the nose for 15 minutes. Thedifference between the absorbent cotton weights is referred as the nasalsecretion, thereby making evaluation.

It can be confirmed by using the following experiment that the presentinvention compounds have immunosuppressant effects. For example, thetherapeutic effects of the present invention compounds on rejection intransplantation can be confirmed by using heart, kidney, liver,pancreas, lung, bone marrow and dermal graft models or the like. As anexample, a heart transplantation model will be illustrated below.

Rat Ectopic Heart Transplantation Model Method:

Using rats, the heart is taken out from a donor rat and transplantedinto the abdomen of a recipient rat. By orally administering a testcompound for a preventive purpose, the heart transplantation survivaldays are estimated and the therapeutic effect can be thus evaluated.

It can be confirmed by using the following experiments that the presentinvention compounds have preventive and/or therapeutic effects onautoimmune diseases. For example, the preventive and/or therapeuticeffects on rheumatoid arthritis (for example, arthritis, arthritisdeformans, etc.) can be confirmed by using the following experiments.

Effect on Rat Collagen-Induced Arthritis Model Method:

Eight-week-old female DA rats (SLC) are used. Throughout theexperimental period, the animals are fed in a feeding room artificiallyconditioned at a temperature of 24±+2° C. and a humidity of 55±5% andcyclically illuminated 12 hours per day. The animals are maintained on asolid feed (CE-2; CLEA Japan) and tap water ad libitum. Afterpre-feeding for 1 week, the animals are used in the experiment. A modelof collagen-induced arthritis is constructed in the following manner.Namely, bovine type II collagen (a 0.3% solution, COLLAGEN GIJUTSUKENSHUKAI; #K-41, lot. 11214, hereinafter referred to as CII) andadjuvant incomplete freund (DIDCO #0639-60, hereinafter referred to asIFA) are mixed at a ratio of CII:saline:IFA of 1:1:2 and the mixture isultrasonically treated (20 sec.×3 times at intervals of 1 min) toprepare an emulsion. This emulsion (0.75 mg of CII/mL) is subcutaneouslyinjected in 0.1 mL portions to 4 sites in the back of the rat. Foradditional sensitization, 0.15 mL thereof emulsion is subcutaneouslyadministered into the tail root to induce arthritis. A test compound issuspended in a 0.5% carboxymethylcellulose solution and orallyadministered by force into the stomach with the use of an oral sondetwice a day (in the morning and evening) from the administration day tothe day 28. The arthritis is evaluated by scoring the arthritis degreein accordance with the method of Ostermann T., et al. (Inflamm. Res.,44, 258-263 (1995)). The foot volume of each individual animal can bemeasured by using a plethysmometer (UNICOM, TK-101CMP).

Mouse Antibody Cocktail-Induced Arthritis Method:

An antibody cocktail against type II collagen is intravenouslyadministered to male DBA/1 JNCrj mice in a dose of 2 mg/0.5 mL/mouse.Three days thereafter, lipopolysaccharide is intraperitoneallyadministered in a dose of 25 μg/0.1 mL/mouse to elicit arthritis. On theday 10, four legs of each animal can be evaluated by scoring in 4-gradesdepending on the intensities of erythema and enlargement. A testcompound is dissolved in an equimolar 0.02 mol/L sodium hydroxidesolution, then diluted with distilled water and orally administeredthrice a day from 30 minutes before the lipopolysaccharideadministration.

Adjuvant-Induced Arthritis Model Method:

Evaluation is made by using 7 weeks male or female Lewis rats. Aftermeasuring the volume of the left hinder leg of a rat, a 600 μg/100 μLsuspension of dry Mycobacterium butyricum cells (Difco), which isemployed as an adjuvant, in liquid paraffin is subcutaneously injectedinto the right hinder foot pad. Thus, a rat adjuvant-induced arthritismodel is constructed. By comparing a test group to which a test compoundhas been orally administered with a control group of non-administration,the therapeutic or preventive effect is evaluated.

Effect of the Present Invention Compound on Pain Response ofAdjuvant-Induced Arthritis Model

The inhibitory effect of a test compound on a pain response of anadjuvant-induced arthritis model (i.e., a chronic arthritis pain model)can be evaluated by using the abnormal phonation response as anindication.

Method:

Seven week male Lewis rats can be used. After measuring the volume ofthe left hinder leg of a rat, a 600 μg/100 μL suspension of dryMycobacterium butyricum cells (Difco), which is employed as an adjuvant,in liquid paraffin is subcutaneously injected into the right hinder footpad. Thus, a rat adjuvant-induced arthritis model is constructed.Twenty-two days after the adjuvant injection, the knee joint of the lefthinder leg is bent and stretched 5 times before orally administering atest compound. Individuals showing the abnormal phonation response everytime are employed in the experiment. Based on the edema volume in theleft hinder leg in the previous day, the rats are divided into groupseach having 10 animals. A test compound at various doses and 5 mL/kg ofan aqueous methylcellulose solution (control) are orally administered.One, two, three and four hours after the administration, the abnormalphonation responses are observed. The analgesic effects are evaluated bybending and stretching the knee joint of the left hinder leg 5 times ateach observation point and individuals showing no abnormal phonationresponse every time are regarded as negative in the abnormal phonationresponse, while individuals showing negative abnormal phonation responseat one or more evaluation points are regarded as positive in theanalgesic effect.

Rabbit Outer Meniscus Removal Model Method:

Rabbits (female Kbs: NZW (Healthy) rabbits) are preliminarily fed for 1week and then subjected to the removal of meniscus by the followingmethod.

A 2% Seractal injection (0.05 ml/kg) is subcutaneously administered intothe back neck of the rabbits. Then, the animals are anesthetized byintravenously administering a Nembutal injection (20 mg/kg) to theauricular edge. The right knee is disinfected with 5-fold iodinetincture dilution, if necessary, the animals are topically anesthetizedby dropping a 2% xylocalne injection into the incised part.

Next, the outer epithelium and articular capsule of the right hinder legare incised at an angle of 90° to the patellar ligament. The outercollateral ligament is excised and then the sesamoid ligament isexcised. In this step, Bosmine injection is dropped for hemostasis. Thetissue bound to the anterior tissue of the outer meniscus is picked upwith forceps and the meniscus is pulled forward and cut at ⅓ in thecenter. The surgical site is washed with saline injection and thesynovial membrane and the articular capsule are stitched. Further themuscular layer and the outer skin are individually stitched.

After the surgical operation, crystalline penicillin G potassium (5000U/animal) and streptomycin sulfate (100 mg/animal) are intramuscularlyinjected into the left hinder leg to prevent infection. The rabbits arefed until they are sacrificed on the day 7 after the surgical operation.During the feeding period, a test compound is administered at eachdefined dose twice a day.

The animals are anesthetized by intravenously injecting a Nembutalinjection (40 mg/kg) into the articular edge and then killed byexsanguination. The right knee joint is collected. The knee joint isincised and the thigh bone and the tibial capital are collected andstored in a 10% neutral buffer Formalin at room temperature. Aftercollecting all samples, the thigh bone and the tibial capital aremasked. Then, the invaded area is measured by using a stereoscopicmicroscope.

Evaluation can be made by a statistically processing method of comparingthe invaded cartilage area of the control (vehicle) group with that ofthe test compound-administered group by Williams's multiple comparison(EXSAS, Ver 5.00).

The above-described experimental model, in which cartilage fractureclosely similar to human arthritis deformans can be induced, has beengenerally accepted as an OA model.

It can be confirmed by using the following experiments that the presentinvention compounds have preventive and/or therapeutic effects onautoimmune diseases. For example, the preventive and/or therapeuticeffects on nerve diseases (multiple sclerosis), inflammatory boweldisease and hepatitis can be confirmed by the following experiments.

EAE Model (Experimental Allergic Encephalomyelitis) Method:

Using Lewis rats, experimental allergic encephalomyelitis is induced byusing various antigens such as spinal cord or MOG (myelinoligodendrocyte elycoprotein). By comparing a group to which a testcompound is orally administered with a non-administered group, atherapeutic or preventive effect can be evaluated.

Acetic Acid-Induced Colitis Model Method:

A required amount of a 5% acetic acid solution is packed into a 1 mLsyringe provided with a disposable oral sonde (for mouse). UnderSomnopentyl anesthesia, the sonde (to 5 cm from the tip) is insertedfrom the anus into the large intestine to into 7-week-old male SD(CD)IGSrats. After the insertion, the 5% acetic acid solution (0.25 mL) isinjected into the large intestine over 10 seconds. Then, the sonde isdrawn and the anus is closed for about 1 minute. A required amount ofsaline is packed into a 50 mL syringe provided with a disposable oralsonde (for mouse). Then, the sonde (to 8 cm from the tip) is insertedfrom the anus into the large intestine. After the insertion, theintestinal tract is washed with the saline (about 10 mL).

A test compound and a vehicle are orally administered each in a definiteamount 30 minutes before the elicitation of colitis and 8 hours afterthe elicitation.

Twenty hours after the elicitation, the animals are sacrificed and thewhole large intestine (from the anus to the cecum root) is taken out.The contents of the large intestine are washed with saline. Aftertrimming the large intestine having been taken out and washed, a part 9cm apart from the anus is excised. From the large intestine piece thusexcised, excessive moisture is wiped off and the wet weight isdetermined by using an electronic balance. The injured area (mm²) of theexcised large intestine is calculated by image analysis.

TNBS-Induced Colitis Model Method:

Under Somnopentyl anesthesia, a flexible oral sonde (to 8 cm from thetip) is inserted from the anus into the large intestine of maleSD(CD)IGS rats (7-week-old). Then, 50 mg TNBS(2,4,6-trinitrobenzenesulfonic acid)/20% ethanol/0.25 mL/rat or 20%ethanol/0.25 mL/rat is injected. After closing the injection site, theanimals are allowed to stand for about 2 hours to thereby elicitcolitis. A test compound is orally administered 30 minutes before theelicitation and 8 hours thereafter on the elicitation day and twice aday (in the morning and evening) from the next day. Three days after theelicitation, the rats are killed by exsanguination under etheranesthesia. The large intestine is taken out and the contents of thelarge intestine are washed with saline. Then, the length of the wholelarge intestine is measured. After trimming the large intestine, a part9 cm apart from the anus is excised. From the large intestine piece thusexcised, excessive moisture is wiped off and the wet weight isdetermined by using an electronic balance.

Chronic Ulcerative Colitis Model Method:

Under pentobarbital anesthesia, 1% aqueous solution of acetic acid (10ml/kg) is injected from the anus into the large intestinal cavity ofmale Syrian hamsters (6 to 7-week-old) by using a flexible oral sondefor rat. Then, the anus is clipped for 30 minutes to thereby elicitcolitis. To a normal group, distilled water is injected in the samemanner. A test compound is orally administered 18 hours and an hourbefore the elicitation of colitis and 6 hours after the elicitation,i.e., thrice in total. Twenty hours after the elicitation, the animalsare sacrificed and a large intestine piece (7 cm from the anus) iscollected. The collected sample is incised along the intestinal tractmembrane attached site and the inside of the intestinal membrane iswashed with saline (5 ml). The incised large intestine is photographedand the ulcer area ratio (total ulcer area×100/total large intestinearea) is calculated. The supernatant of the large intestine washingliquor is used in an occult blood test.

Effect of Inhibiting Chronic Ulcerative Colitis Method:

Male C57BL/6 mice are maintained on 7% aqueous solution of dextransulfate sodium (hereinafter referred to as DSS) ad libitum. From theinitiation of the aqueous DSS solution intake, the body weight andclinical score are measured every other day. The clinical score iscalculated as the sum of diarrhea score (normal: 0, loose stool: 2,diarrhea: 4) and hematochezia score (normal: 0, hemorrhage: 2, serioushemorrhage: 4). On the day 10 of the aqueous DSS solution intake,heparinized blood is collected from the postcava under ether anesthesia.By using a blood cell counter, the hematocrit value is measured. Fromthe day 0 to the day 10 of the aqueous DSS solution intake, a testcompound is orally administered repeatedly in a definite dose twice aday.

Inhibitory Effect on Galactosamine/LPS-Induced Hepatopathy Model Method:

A test compound at various concentrations is administered to male mouse(BALB/c, 7 to 8-week-old) having been fasted overnight. Thirty minutesthereafter, a solution of a mixture of galactosamine (700 mg/kg) and LPS(10 μg/kg) (Bacto W. E. coli 055:B5; manufactured by DIFCO Lab.) isintraperitoneally administered to elicit hepatopathy. Each test compoundis suspended in 0.5% methylcellulose.

Seven hours after the elicitation, heparinized blood is collected fromthe aorta abdominalis under ether anesthesia. Then, the plasma isimmediately prepared. The extent of hepatopathy is evaluated by using anincrease in plasma GPT as an indication. The plasma GPT is measured withan autoanalyzer with the use of a GPT measurement reagent (manufacturedby Wako Pure Chemicals). By referring a difference in plasma GPT levelbetween an untreated group and the hepatopathy-induced group as to 100%,the inhibitory ratio (%) of the test compound can be calculated.

It can be confirmed that the present invention compounds have preventiveand/or therapeutic effects on multiple organ failure and sepsis by usingthe following experiment.

Multiple Organ Failure Model Method:

Rats having been fasted for about 24 hours are anesthetized byintravenously administering pentobarbital (40 mg/kg). After fittingcatheters to both femoral veins and an alar needle to the tail vein,lipopolysaccharide (LPS; 0.3 mg/kg/h) and a test compound or a vehiclefor the administration of the test compound (in the case of a controlgroup) are continuously administered via an arbitrary vein. During theadministration period, the animals are additionally anesthetized, ifnecessary depending on the wakening. Six hours after the initiation ofthe continuous intravenous administration, the blood is collected fromthe aorta abdominalis. Then, elastase activity, coagulation fibrinolysisparameters (fibrinogen, FDP, platelet count, etc.) and biochemicalparameters of blood (GOT, GPT, creatinine, BUN, etc.) are measured.Further, an indication of lung injury is determined by taking out lungsand measuring the wet weight or measuring the leakage protein which issystemically administering a fluorescent labeled protein into the lung.

(IV) Experiments for Evaluating the Inhibitory Effect of the PresentInvention Compound on Drug Metabolic Enzyme and/or the Inhibitory Effecton the Induction of Drug Metabolic Enzyme

CYP1A2 Inhibitory Effect Using Expression Microsome Method:

A CYP1A2 expression microsome (Gentest) prepared by expressing in humanlymphoblast cells is employed as an enzyme system. As a fluorescentsubstrate, 3-cyano-7-ethoxycoumarin (CEC, Molecular Probes) is employed.

As a reaction system, use is made of a phosphate buffer (100 mmol/l, 200μl; pH 7.4) containing the CYP1A2 expression microsome (0.05 mg/ml),MgCl₂ (5 mmol/l) and NADPH (1 mmol/l). To this reaction system, thefluorescent substrate CEC (final concentration 10 μmol/l) and a testcompound (final concentration 3, 10 or 30 μmol/l) or α-naphthoflavone(final concentration 0.003 or 0.01 μmol/l; TOKYO KASEI) employed as apositive control inhibitor are added and the reaction is performed at37° C. for 30 minutes. The fluorescent intensity (Ex=409 nm, Em=409 nm)of a metabolite of the substrate is measured (fluorescence detector:Spectra Max Geminin (Molecular Devices)).

The inhibitory effect is evaluated in the inhibition ratio (%) byreferring the inhibition of the formation of the metabolite by the testcompound as an indication.

Inhibitory Activity Against Human CYP2C9 Method:

Inhibitory activity against human CYP2C9 of the compound of the presentinvention can be evaluated by a method of Sato, et al. (Yakubutsudotai(Xenobio. Metabol. and Dispos.), 16(2), 115-126 (2001)), which isimproved in assaying accuracy and/or assaying sensitivity.

Inhibitory Activity Against Human CYP3A4 Method:

Inhibitory activity against human CYP3A4 of the compound of the presentinvention can be evaluated by an improved method described in DrugMetabolism and Disposition, 28(12), 1440-1448 (2000).

For example, a reaction solution consisted of potassium phosphate buffer(pH 7.4) (final concentration: 200 mM), magnesium chloride hexahydrate(final concentration: 5 mM), substrate (7-benzyloxyquinoline (7-BQ),final concentration: 40 μM), and expression system microsome(Daiichikagakuyakuhin, final concentration: 0.25 mg/mL) is prepared.Then, 100 μL of the reaction solution is dispensed in 96 well plate, andadded by 50 μL of an aqueous solution containing test a compound and0.8% acetonitrile, to carry out 10 minutes of preincubation at 37° C.Then, 50 μL of a reduced nicotinamide adenine dinucleotide phosphate(NADPH, 4 mM) is added to initiate a reaction. The fluorescenceintensity of each well is measured at the time when NADPH is added andafter incubated for 30 minutes. Excitation wavelength at 409 nm andemission wavelength at 530 nm of quinolinol, which is metabolite ofsubstrate, is measured. Inhibition ratio (%) of the test compound iscalculated by the following calculation formula to obtain IC₅₀ value.

Inhibition ratio(%)=[1−{(measured value when a test compound isadded)−(blank value)/(control value−blank value)}]×100

Human CYP3A4 Inducing Effect Method:

HepG2 cells are cultured in an incubator at 37° C. and 5% CO₂ by using amedium (MEM(+)) prepared by mixing minimum essential medium Eagle (MOD.)with Earle's salts without L-glutathione (manufactured by ICN, productNo. 1210254) with 1/100 times as much non-essential amino acids for MEMEagle (100×) (manufactured by ICN, product No. 1681049),Antibiotic-Antimycotic ((100×), manufactured by GIBCO, product No.15240-096), L-glutamine-200 mM ((100×), GIBCO, product No. 25030-081)and 1/10 times as much fetal bovine serum (Sigma, product No. F9423).The medium is replaced at intervals of 2 to 3 days and an about ⅕portion of the cells attaining a confluence are subcultured once a week.Almost confluent HepG2 cells having been cultured in a culture flask(225 cm²) are seeded in a 24-well plate (IWAKI, product No. 3820-024) ata density of 5×10⁴ cells/MEM(+) 500 μL/well and cultured in an incubatorat 37° C. and 5% CO₂ for 2 days. Subsequently, transduction is carriedout as follows. Per well (MEM 100 μl) of the 24-well plate, a solutioncontaining autogenously prepared hPXR vector (10 ng), CYP3A4 vector (200ng) and pRL-TK vector (200 ng) and preliminarily prepared Tfx(Tradename)-20 reagent (0.75 μL, Promega, product No. E2391, prepared inaccordance with the attached manual) are added. After mixing byupsetting several times, the mixture is allowed to stand at roomtemperature for 15 minutes (DNA-liposome mixture solution). Cells havingbeen cultured for 2 days are washed with PBS(−) (1 mL per well) and thenthe DNA-liposome mixture solution prepared above (100 μl) is added.After culturing the cells in an incubator at 37° C. and 5% CO₂ for 1hour, MEM(+) (440 μL/well) and a test compound (adjusted to a 10-foldconcentration of the final concentration by using MEM(+) containing 1%DMSO, 60 μl/well) is added and the cells are cultured in an incubator at37° C. and 5% CO₂ for additional 2 days. Then, the cells having beencultured for 2 days after the addition of the test compound are washedwith PBS(−) (1 mL per well) once and a passive lysis buffer (PLB) (100μl/well) is added. The mixture is allowed to stand at room temperaturefor 15 minutes or longer (lysis solution). A 20 μl/well portion of thelysis solution thus prepared is transferred into a 96-well white plate(Perkin Elmer, product No. 23300) and a luciferase assay reagent II(LARII) (100 μl/well) is added. After 2 to 24 seconds, a stop & gloreagent (100 μl/well) is added and then each chemical luminescence ismeasured for 2 to 14 seconds by using a luminometer (Microlumat LB96P,Berthold JAPAN). The reagents employed (PLB, LARII and the stop & gloreagent) are prepared and handled in accordance with the manual attachedto Dual-Luciferase^(R) Reporter Assay System (Promega, product No.E1910).

The CYP3A4 inducing activity is calculated by referring an increase inthe CYP3A4 transcriptional activity in the case of using Rifampicin (10μmol/L) as a positive control as to 100%.

(V) Experiments for Evaluating the Toxicity of the Present InventionCompound Mutagenicity Test

The mutagencities of the present invention compounds can be evaluated inaccordance with the method described in Anei-ho ni Okeru HenigenseiShiken-Tesuto Gaidorain to GLP (Mutagenicity Test according toOccupational Health and Safety Law-Test Guideline and GLP-) (Ed. byChemical Substance Investigation Division, Industrial Safety and HealthDepartment, Ministry of Labor; Japan Industrial Safety and HealthAssociation, 1991, chapter 4).

Single Acute Toxicity Test in Rat

The test compound is administered to six-week-old Crj:CD (SD) rat bysingle intravenous dose or single oral administration. Toxicity can beevaluated by contrast with value at no addition of the test compound.Basic evaluation of toxicity can be done by, for example, observation ofperformance status or locomotor activity, etc.

Cardiotoxicity to Rat (Bradycardia)

Using SD rats, catheters are inserted into the jugular vein and thecarotid artery (or the femoral vein and the femoral artery) underanesthesia. The tip of the arterial cannula is connected to a pressuretransducer (DX-100, NIHON KOHDEN) and the blood pressure and the heartrate are measured respectively via a strain pressure amplifier (AP-641G,NIHON KOHDEN) and an instant heart rate meter (AT-601G, NIHON KOHDEN).Under anesthesia or promoting wakening, a test compound is intravenouslyor orally administered and changes in the blood pressure and heart rateare monitored.

(ii) Evaluation of the Activity of the Compound of the Present InventionAgainst hERG I_(Kr) Current

Method

According to the report by Zou, et al. (Biophys. J., 74, 230-241(1998)), using HEK293 cell overexpressed of human ether-a-go-go-relatedgene (hERG), max tale current of hERG I_(Kr) current induced bydepolarization pulse, followed by repolarization pulse is measured bypatch-clamp recording. Rate of change (inhibition ratio) is calculatedby comparison max tale current between before addition of the testcompound and 10 minutes after. The influence of the test compoundagainst hERG I_(Kr) current can be evaluated by the inhibition ratio.

Processes for the Preparation of the Compound of the Present Invention:

The compound represented by formula (I) in the present invention can beprepared by methods which properly improved and combined known methods,such as methods described in WO02/092068, Synth. Commun., 33(19), 3347(2003), Comprehensive Organic Transformations: A Guide to FunctionalGroup Preparations, 2nd Ed., (Richard C. Larock, John Wiley & Sons Inc.(1999)) and the like, methods described below and/or method accordingthereto, or methods described in Examples. In each method describedbelow, a starting material can be used as a salt thereof. An example ofthe salt includes a variety of salt described as a salt of compoundrepresented by formula (I) described above.

Among the compounds represented by formula (I), a compound wherein X isbound to ring B via oxygen, i.e., a compound represented by formula(I-D):

wherein X′ represents a bond or a spacer having 1 to 7 atoms in its mainchain; and other symbols have the same meanings as described above;

can be prepared by the following method (1) or (2).

(1) A compound represented by formula (I-D) can be prepared bysubjecting a compound represented by formula (II):

wherein all symbols have the same meanings as described above;

and a compound represented by formula (III):

wherein R²⁸ represents a hydrogen atom or a group for protecting acarboxy group; and other symbols have the same meanings as describedabove;

to Mitsunobu reaction, followed by a removal of the protecting group, ifnecessary. This Mitsunobu reaction, which is publicly known, is carriedout by, for example, reacting these compounds at 0 to 60° C. in anorganic solvent (dichloromethane, diethyl ether, tetrahydrofuran,acetonitrile, benzene, toluene, etc.) in the presence of an azo compound(diethyl azodicarboxylate (DEAD), diisopropyl azodicarboxylate,1,1′-(azodicarbonyl)dipiperidine, 1,1′-azobis(N,N-dimethylformamide),etc.) and a phosphine compound (triphenylphosphine, tributylphosphine,trimethylphosphine, polymer supported triphenylphosphine, etc.). Theremoval of the group for protecting a carboxy group can be carried outby a known method, for example, the method described in WO 02/092068 ora similar method and/or the method described in Protective Groups inOrganic Synthesis, T. W. Greene, John Wiley & Sons Inc. (1999). Thegroup for protecting a carboxy group is not particularly restricted anduse may be made of an arbitrary one in addition to the above-describedgroups so long as it can be easily and selectively removed.

(2) A compound represented by formula (I-D) can be prepared bysubjecting a compound represented by formula (II):

wherein all symbols have the same meanings as described above;

and a compound represented by formula (IV):

wherein L represents a leaving group such as a halogen atom,methanesulfonyloxy (OMs), toluenesulfonyloxy (OTs),trifluoromethanesulfonyloxy (OTf), alkylthio, alkylsulfinyl,alkylsulfonyl or hydroxysulfonyl; and other symbols have the samemeanings as described above;

or a compound represented by formula (V):

wherein all symbols have the same meanings as described above;

and a compound represented by formula (III):

wherein all symbols have the same meanings as described above;

respectively to etherifying reactions, followed by a removal of theprotecting group, if necessary. These etherifying reactions, which havebeen publicly known, are carried out by, for example, reacting thecompounds at 0 to 100° C. in an organic solvent (N,N-dimethylformamide,dimethyl sulfoxide, chloroform, dichloromethane, diethyl ether,tetrahydrofuran, methyl t-butyl ether, etc.) in the presence of analkali metal hydroxide (sodium hydroxide, potassium hydroxide, lithiumhydroxide, etc.), an alkaline earth metal hydroxide (barium hydroxide,calcium hydroxide, etc.) or a carbonate (sodium carbonate, potassiumcarbonate, cesium carbonate, etc.), an aqueous solution thereof or amixture thereof. The removal of the protecting group can be carried outby a similar method to those described above.

Among the present invention compounds represented by formula (I), acompound wherein Y represents:

wherein Y² and Y³ each independently represents a bond or a spacerhaving 1 to 8 atoms in its main chain (provided that the sum of theatoms in its main chains of Y² and Y³ does not exceed 8); and R⁷represents a hydrogen atom or a substituent or an atom in the spacerrepresented by Y² may be taken together with R⁷ to form a heterocyclicgroup which may have a substituent(s);

namely, a compound represented by formula (I-E):

wherein all symbols have the same meanings as described above;

can be prepared by subjecting a compound represented by formula (VI):

wherein all symbols have the same meanings as described above;

and a compound represented by formula (VII):

wherein all symbols have the same meanings as described above;

to a reductive amination reaction, followed by a removal of theprotecting group, if necessary. This reductive amination reaction, whichhas been publicly known, is carried out by, for example, reacting thecompounds at a temperature of 0 to 100° C. in an organic solvent(N,N-dimethylformamide, dichloromethane, etc. either alone or as a mixedsolvent comprising two or more of these solvent at an arbitrary mixingrate) in the presence or absence of an organic acid (acetic acid, etc.)or in the presence or absence of an organic base (triethylamine, sodiumhydrogencarbonate, etc.) with the use of a reducing agent (sodiumtriacetoxyborohydride, sodium cyanoborohydride, tetrabutylammoniumborohydride, etc.). The removal of the protecting group can be carriedout by a similar method to those described above.

Among the present invention compounds represented by formula (I), acompound wherein Y represents:

wherein all symbols have the same meanings as described above;

namely, a compound represented by formula (I-F):

wherein all symbols have the same meanings as described above;

can be prepared by subjecting a compound represented by formula (VIII):

wherein all symbols have the same meanings as described above;

and a compound represented by formula (IX):

L—Y²—COOR²⁸  (IX)

wherein all symbols have the same meanings as described above;

or a compound represented by formula (X):

wherein all symbols have the same meanings as described above;

and a compound represented by formula (XI):

wherein all symbols have the same meanings as described above;

respectively to alkylation reactions, followed by a removal of theprotecting group, if necessary. These alkylation reactions, which havebeen publicly known, are carried out by, for example, reacting thecompounds at 0 to 100° C. in an organic solvent (N,N-dimethylformamide,dimethyl sulfoxide, chloroform, dichloromethane, diethyl ether,tetrahydrofuran, methyl t-butyl ether, etc.) in the presence of analkali metal hydroxide (sodium hydroxide, potassium hydroxide, lithiumhydroxide, etc.), an alkaline earth metal hydroxide (barium hydroxide,calcium hydroxide, etc.) or a carbonate (sodium carbonate, potassiumcarbonate, cesium carbonate, etc.), an aqueous solution thereof or amixture thereof. The removal of the protecting group can be carried outby a similar method to those described above.

Among the present invention compounds represented by formula (I), acompound wherein Y represents:

wherein Y⁴ represents a bond or a spacer having 1 to 7 atoms in its mainchain; R²⁹, R³⁰ and R³¹ each independently represents a hydrogen atom ora substituent; and other symbols have the same meanings as describedabove;

namely, a compound represented by formula (I-G):

wherein all symbols have the same meanings as described above;

can be prepared by subjecting a compound represented by formula (XII):

wherein all symbols have the same meanings as described above;

and a compound represented by formula (XIII):

wherein all symbols have the same meanings as described above;

to an addition reaction to amine, followed by a removal of theprotecting group, if necessary. The addition reaction to amine, whichhas been publicly known, is carried out by, for example, reacting thecompounds at a temperature of −78° C. to the reflux temperature in anorganic solvent (for example, methanol, ethanol, propanol, benzene,toluene, diethyl ether, tetrahydrofuran, dimethoxyethane, etc.) orwithout solvent. The removal of the protecting group can be carried outby a similar method to those described above.

The compounds represented by the formulae (II) to (XIII) which are usedas the starting materials in the present invention are either publiclyknown per se or can be easily prepared by publicly known methods.

In each reaction of the specification, it may be used a solid phasereagent which is supported by polymer (for example, polystyrene,polyacrylamide, polypropylene or polyethyleneglycol etc.).

In each reaction of the specification, the obtained products may bepurified by conventional techniques. For example, the purification maybe carried out by distillation at atmospheric or reduced pressure, byhigh performance liquid chromatography with silica gel or magnesiumsilicate, by thin layer chromatography, by ion-exchange resin, byscavenger resin, by column chromatography, by washing or byrecrystallization. The purification may be done each reaction or afterseveral reactions.

Application to Pharmaceuticals:

The compounds having an ability to bind to an S1P receptor (inparticular, EDG-6, preferably EDG-1 and EDG-6) are useful asimmunosuppressants. The binding manner to EDG-1 is preferably anagonistic action.

The present invention compounds represented by formula (I), saltsthereof, solvates thereof or prodrugs thereof are compounds having anability to bind to EDG-6 and exhibit prolonged pharmacological action.Therefore, they are useful as preventives and/or remedies in mammals, inparticular, humans for rejection in transplantation, rejection of atransplanted organ, transplantation versus host disease, autoimmunediseases (systemic lupus erythematosus, rheumatoid arthritis, myastheniagravis and the like), allergic diseases (atopic dermatitis, asthma andthe like), inflammation, infection, ulcer, lymphoma, malignant tumor,leukemia, arteriosclerosis, acute heart failure, angina, stroke,traumatic injury, genetic diseases and the like.

In addition to the ability to bind to EDG-6, some of the presentinvention compounds have an agonistic activity against EDG-1 and,therefore, show an immunosuppressant effect and prolongedpharmacological action. Owing to these characteristics, they are moreuseful as preventives and/or remedies for rejection in transplantation,transplantation versus host disease, autoimmune diseases, allergicdiseases and the like.

When the compound represented by formula (I) in the present invention ora combination preparation of the compound of the present inventionrepresented by formula (I) and other drug(s) is used for the purposeabove described, it may be normally administered systemically orlocally, usually by oral or parenteral administration. The doses to beadministered are determined depending upon, for example, age, bodyweight, symptom, the desired therapeutic effect, the route ofadministration, and the duration of the treatment. In the human adult,the doses per person are generally from 1 ng to 100 mg, by oraladministration, up to several times per day, and from 0.1 ng to 100 mg,by parenteral administration, up to several times per day, or continuousadministration from 1 to 24 hours per day from vein. As described above,the doses to be used depend upon various conditions. Therefore, thereare cases in which doses lower than or greater than the ranges specifiedabove may be used.

When the compound represented by formula (I) in the present invention ora combination preparation of the compound of the present inventionrepresented by formula (I) and other drug(s) is administered, it is usedin the form of solid for oral administration, liquid forms for oraladministration, injections, liniments, suppositories, eye drops orinhalant for parenteral administration or the like.

Solid forms for oral administration include compressed tablets, pills,capsules, dispersible powders, and granules. Capsules include hardcapsules and soft capsules. Tablets include sublingual tablets, buccaladhesive tablets, buccal quick disintegration tablets and or the like.Also, in such solid forms, one, two or more active compound(s) may beadmixed with a vehicle (such as lactose, mannitol, glucose,microcrystalline cellulose or starch), a binder (such ashydroxypropylcellulose, polyvinylpyrrolidone or magnesium metasilicatealuminate), a disintegrant (such as cellulose calcium glycolate),lubricants (such as magnesium stearate), a stabilizing agent, and asolution adjuvant (such as glutamic acid or aspartic acid) and preparedaccording to methods well known in normal pharmaceutical practice. Thesolid forms may, if desired, be coated with a coating agent (such assugar, gelatin, hydroxypropylcellulose or hydroxypropylmethylcellulosephthalate), or be coated with two or more films. Furthermore, coatingmay include containment within capsules of absorbable materials such asgelatin.

The sublingual tablets are produced in accordance with a conventionallyknown method. For example, one, two or more active substance(s) are usedafter making into pharmaceutical preparations by the law of the art bymixing with an vehicle (such as lactose, mannitol, glucose,microcrystalline cellulose, colloidal silica, starch, etc.), a binder(such as hydroxypropylcellulose, polyvinylpyrrolidone, magnesiumaluminometasilicate, etc.), a disintegrant (such as starch,L-hydroxypropylcellulose, carboxymethylcellulose, croscarmellose sodium,cellulose calcium glycolate, etc.), a lubricant (such as magnesiumstearate, etc.), a swelling agent (such as hydroxypropylcellulose,hydroxypropylmethylcellulose, carbopol, carboxymethylcellulose,polyvinyl alcohol, xanthan gum, guar gum, etc.), a swelling adjuvant(such as glucose, fructose, mannitol, xylitol, erythritol, maltose,trehalose, phosphate, citrate, silicate, glycine, glutamic acid,arginine, etc.), a stabilizing agent, a solubilizing agent (such aspolyethylene glycol, propylene glycol, glutamic acid, aspartic acid,etc.), a flavoring agent (such as orange, strawberry, mint, lemon,vanilla, etc.) and the like. Also, if necessary, they may be coated witha coating agent (such as sucrose, gelatin, hydroxypropylcellulose,hydroxypropylmethylcellulose phthalate, etc.), or coated with two ormore films. In addition, if necessary, a preservative, an antioxidant, acolorant, a sweetening agent and the like generally used additive agentscan also be added thereto.

The buccal adhesive tablets are produced in accordance with aconventionally known method. For example, one, two or more activesubstance(s) are used after making into pharmaceutical preparations bythe law of the art by mixing with an vehicle (such as lactose, mannitol,glucose, microcrystalline cellulose, colloidal silica, starch, etc.), abinder (such as hydroxypropylcellulose, polyvinylpyrrolidone, magnesiumaluminometasilicate, etc.), a disintegrant (such as starch,L-hydroxypropylcellulose, carboxymethylcellulose, croscarmellose sodium,cellulose calcium glycolate, etc.), a lubricant (such as magnesiumstearate, etc.), an adhesive agent (such as hydroxypropylcellulose,hydroxypropylmethylcellulose, carbopol, carboxymethylcellulose,polyvinyl alcohol, xanthan gum, guar gum, etc.), an adhesive adjuvant(such as glucose, fructose, mannitol, xylitol, erythritol, maltose,trehalose, phosphate, citrate, silicate, glycine, glutamic acid,arginine, etc.), a stabilizing agent, a solubilizing agent (such aspolyethylene glycol, propylene glycol, glutamic acid, aspartic acid,etc.), a flavoring agent (such as orange, strawberry, mint, lemon,vanilla, etc.) and the like. Also, if necessary, they may be coated witha coating agent (such as sucrose, gelatin, hydroxypropylcellulose,hydroxypropylmethylcellulose phthalate, etc.), or coated with two ormore layers. In addition, if necessary, a preservative, an antioxidant,a colorant, a sweetening agent and the like generally used additiveagents can also be added thereto.

The buccal quick disintegration tablets are produced in accordance witha conventionally known method. For example, one, two or more activesubstance(s) are used as such or after making into pharmaceuticalpreparations by the law of the art by mixing the active substances,prepared by coating the material powder or granulated material particleswith an appropriate coating agent (such as ethyl cellulose,hydroxypropylcellulose, hydroxypropylmethylcellulose,acrylate-methacrylate copolymer, etc.) and a plasticizer (such aspolyethylene glycol, triethyl citrate, etc.), with an vehicle (such aslactose, mannitol, glucose, microcrystalline cellulose, colloidalsilica, starch, etc.), a binder (such as hydroxypropylcellulose,polyvinylpyrrolidone, magnesium aluminometasilicate, etc.), adisintegrant (such as starch, L-hydroxypropylcellulose,carboxymethylcellulose, croscarmellose sodium, cellulose calciumglycolate, etc.), a lubricant (such as magnesium stearate, etc.), adispersing adjuvant (such as glucose, fructose, mannitol, xylitol,erythritol, maltose, trehalose, phosphate, citrate, silicate, glycine,glutamic acid, arginine, etc.), a stabilizing agent, a solubilizingagent (such as polyethylene glycol, propylene glycol, glutamic acid,aspartic acid, etc.), a flavoring agent (such as orange, strawberry,mint, lemon, vanilla, etc.) and the like. Also, if necessary, they maybe coated with a coating agent (such as sucrose, gelatin,hydroxypropylcellulose, hydroxypropylmethylcellulose phthalate, etc.),or coated with two or more layers. In addition, if necessary, apreservative, an antioxidant, a colorant, a sweetening agent and thelike generally used additive agents can also be added thereto.

Liquid forms for oral administration include pharmaceutically acceptablesolutions, suspensions, emulsions, syrups and elixirs. In such forms,one, two or more active compound(s) may be dissolved, suspended oremulized into diluent(s) commonly used in the art (such as purifiedwater, ethanol or a mixture thereof). Besides such liquid forms may alsocomprise some additives, such as wetting agents, suspending agents,emulsifying agents, sweetening agents, flavoring agents, aroma,preservative or buffering agent.

The agent for parenteral administration may be in the form of, e.g.,ointment, gel, cream, wet compress, paste, liniment, nebula, inhalant,spray, eye drops, collunarium or the like. These agents each contain oneor more active materials and are prepared by any known method orcommonly used formulation.

The ointment is prepared by any known or commonly used formulation. Forexample, one, two or more active materials are titurated or dissolved ina base to prepare such an ointment. The ointment base is selected fromknown or commonly used materials. In some detail, higher aliphatic acidor higher aliphatic acid ester (e.g., myristic acid, palmitic acid,stearic acid, oleic acid, myristic acid ester, palmitic acid ester,stearic acid ester, oleic acid ester), wax (e.g., beeswax, whale wax,ceresin), surface active agent (e.g.,polyoxyethylenealkyletherphosphoric acid ester), higher alcohol (e.g.,cetanol, stearyl alcohol, setostearyl alcohol), silicon oil (e.g.,dimethyl polysiloxane), hydrocarbon (e.g., hydrophilic petrolatum, whitepetrolatum, purified lanolin, liquid paraffin), glycol (e.g., ethyleneglycol, diethylene glycol, propylene glycol, polyethylene glycol,macrogol), vegetable oil (e.g., castor oil, olive oil, sesame oil,turpentine oil), water, absorption accelerator and rash preventive maybe used singly or in admixture of two or more thereof. The base mayfurther comprise a humectant, a preservative, a stabilizer, anantioxidant, a perfume, etc.

The gel is prepared by any known or commonly used formulation. Forexample, one, two or more active materials are dissolved in a base toprepare such a gel. The gel base is selected from known or commonly usedmaterials. For example, lower alcohol (e.g., ethanol, isopropylalcohol), gelling agent (e.g., carboxymethylcellulose,hydroxyethylcellulose, hydroxypropylcellulose, ethylcellulose),neutralizing agent (e.g., triethanolamine, diisopropanolamine), surfaceactive agent (e.g., polyethylene glycol monostearate), gum, water,absorption accelerator, and rash preventive are used singly or inadmixture of two or more thereof. The gel base may further comprise ahumectant, an antioxidant, a perfume, etc.

The cream is prepared by any known or commonly used formulation. Forexample, one, two or more active materials are dissolved in a base toprepare such a cream. The cream base is selected from known or commonlyused materials. For example, higher aliphatic acid ester, lower alcohol,hydrocarbon, polyvalent alcohol (e.g., propylene glycol, 1,3-butyleneglycol), higher alcohol (e.g., 2-hexyldecanol, cetanol), emulsifier(e.g., polyoxyethylene alkyl ether, aliphatic acid ester), water,absorption accelerator, and rash preventive are used singly or inadmixture of two or more thereof. The cream base may further comprise ahumectant, an antioxidant, a perfume, etc.

The wet compress is prepared by any known or commonly used formulation.For example, one, two or more active materials are dissolved in a baseto prepare a kneaded mixture which is then spread over a support toprepare such a wet compress. The wet compress base is selected fromknown or commonly used materials. For example, thickening agent (e.g.,polyacrylic acid, polyvinyl pyrrolidone, gum arabic, starch, gelatin,methylcellulose), wetting agent (e.g., urea, glycerin, propyleneglycol), filler (e.g., kaolin, zinc oxide, talc, calcium, magnesium),water, dissolution aid, tackifier, and rash preventive may be usedsingly or in admixture of two or more thereof. The wet compress base mayfurther comprise a humectant, an antioxidant, a perfume, etc.

The pasting agent is prepared by any known or commonly used formulation.For example, one or more active materials are dissolved in a base toprepare a kneaded mixture which is then spread over a support to preparesuch a pasting agent. The pasting agent base is selected from known orcommonly used materials. For example, polymer base, fat and oil, higheraliphatic acid, tackifier and rash preventive may be used singly or inadmixture of two or more thereof. The pasting agent base may furthercomprise a humectant, an antioxidant, a perfume, etc.

The liniment is prepared by any known or commonly used formulation. Forexample, one, two or more active materials are dissolved, suspended oremulsified in water, alcohol (e.g., ethanol, polyethylene glycol),higher aliphatic acid, glycerin, soap, emulsifier, suspending agent,etc., singly or in combination of two or more thereof, to prepare such aliniment. The liniment may further comprise a humectant, an antioxidant,a perfume, etc.

The nebula, inhalant, spray and aerosol each may comprise a stabilizersuch as sodium hydrogensulfite and a buffer capable of providingisotonicity such as isotonic agent (e.g., sodium chloride, sodiumcitrate, citric acid). For the process for the preparation of spray,reference can be made to U.S. Pat. Nos. 2,868,691 and 3,095,355.

The injection for parenteral administration may be in the form ofsolution, suspension, emulsion or solid injection to be dissolved orsuspended in a solvent in use. The injection is prepared by dissolving,suspending or emulsifying one, two or more active materials in asolvent. As such a solvent there may be used distilled water forinjection, saline, vegetable oil, alcohol such as propylene glycol,polyethylene glycol and ethanol, etc., singly or in combination. Theinjection may further comprise a stabilizer, a dissolution aid (e.g.,glutamic acid, aspartic acid, Polysolvate 80 (trade name)), a suspendingagent, an emulsifier, a soothing agent, a buffer, a preservative, etc.The injection is sterilized at the final step or prepared by an asepticprocess. Alternatively, an aseptic solid agent such as freeze-driedproduct which has previously been prepared may be rendered aseptic ordissolved in an aseptic distilled water for injection or other solventbefore use.

The eye drops for parenteral administration may be in the form ofliquid, suspension, emulsion or ointment or may be dissolved in asolvent in use. These eye drops are prepared by any known method. Forexample, one, two or more active materials are dissolved, suspended oremulsified in a solvent. As such a solvent for eye drops there may beused sterilized purified water, saline and other aqueous or nonaqueoussolvents (e.g., vegetable oil), singly or in combination. The eye dropsmay comprise an isotonic agent (e.g., sodium chloride, concentratedglycerin), a buffering agent (e.g., sodium phosphate, sodium acetate), asurface active agent (e.g., Polysolvate 80 (trade name), polyoxylstearate 40, polyoxyethylene-hardened castor oil), a stabilizer (sodiumcitrate, sodium edetate), a preservative (e.g., benzalconium chloride,Paraben), etc. properly selectively as necessary. The eye drops aresterilized at the final step or prepared by an aseptic process.Alternatively, an aseptic solid agent such as freeze-dried product whichhas previously been prepared may be rendered aseptic or dissolved in anaseptic distilled water for injection or other solvent before use.

The inhalant for parenteral administration may be in the form ofaerosol, powder for inhalation or liquid for inhalation. The liquid forinhalation may be dissolved or suspended in water or other proper mediumin use. These inhalants are prepared by an known method. For example,the liquid for inhalation is prepared from materials properly selectedfrom preservatives (e.g., benzalconium chloride, Paraben), colorants,buffering agents (e.g., sodium phosphate, sodium acetate), isotonicagents (e.g., sodium chloride, concentrated glycerin), thickening agents(e.g., carboxyvinyl polymer), absorption accelerators, etc. asnecessary.

The powder for inhalation is prepared from materials properly selectedfrom glidants (e.g., stearic acid and salt thereof), binders (e.g.,starch, dextrin), vehicles (e.g., lactose, cellulose), colorants,preservatives (e.g., benzalconium chloride, Paraben), absorptionaccelerators, etc., if necessary.

In order to administer the liquid for inhalation, a sprayer (e.g.,atomizer, nebulizer) is normally used. In order to administer the powderfor inhalation, a powder inhaler is normally used.

Other examples of the composition for oral administration includesublingual medication for sublingual administration, suppository forrectal administration and pessary for vaginal administration prepared byan ordinary formulation comprising one or more active materials.

The compound of the present invention of formula (I) may be administeredas a combined preparation by combining with other pharmaceuticals forthe purpose of

1) supplement and/or enhancing of prevention and/or treatment effect ofthe compound,2) improvement in pharmacokinetics and absorption and reduction of doseof the compound,and/or3) reduction of side effect of the compound.

The combined preparation of the compound of the present invention offormula (I) with other pharmaceuticals may be administered in a form ofa compounded agent in which both components are compounded in apreparation or may be in a form in which they are administered by meansof separate preparations. The case of administration by means ofseparate preparations includes a simultaneous administration andadministrations with time difference. In the case of administrationswith time difference, the compound of the present invention of formula(I) may be firstly administered, followed by administering the otherpharmaceutical or the other pharmaceutical may be administered firstly,followed by administering the compound of the present invention offormula (I). Methods for each of the administration are the same ordifferent.

The combination preparation with other pharmaceuticals which supplementand/or enhance the prevention and/or treatment effect of the compound ofthe present invention is not limited to those exemplified in the presentinvention. Also, the combination preparation with other pharmaceuticalswhich supplement and/or enhance the prevention and/or treatment effectof the compound of the present invention, not only that which has beenfound up to now but also that which will be found in future on the basisof the above-described mechanism are included.

The diseases against which the combined drugs as described above havepreventive and/or therapeutic effects are not particularly restricted.Namely, they may be diseases by which the preventive and/or therapeuticeffects of the present invention compounds represented by formula (I)can be complemented and/or enhanced. For example, otherimmunosuppressants, antibiotics, etc. may be cited as drugs to be usedfor complementing and/or enhancing the preventive and/or therapeuticeffects on rejection in transplantation to which an EDG-6 agonist isapplicable. Steroids, nonsteroidal anti-inflammatory drugs (NSAIDs),disease modifying antirheumatic diseases (DMARDs, slow-actingantirheumatic drugs), other immunosuppressants, T cell inhibitors,anti-inflammatory enzyme preparations, cartilage protecting agents,prostaglandins, prostaglandin synthase inhibitors, IL-1 inhibitors, IL-6inhibitors (including protein preparations such as an anti-IL-6 receptorantibody), TN-α inhibitors (including protein preparations such as ananti-TNF-α antibody), interferon γ agonists, phosphodiesteraseinhibitors, metalloproteinase inhibitors and the like can be cited asdrugs to be used in preventing and/or treating autoimmune diseases.EDG-6 agonists can be used in combination with them. Concerning drugs tobe used for complementing and/or enhancing the preventive and/ortherapeutic effects on allergic diseases, examples of drugs to be usedfor complementing and/or enhancing the preventive and/or therapeuticeffects on atopic dermatitis include immunosuppressants, steroids,nonsteroidal anti-inflammatory drugs, prostaglandins, antiallergicagents, mediator release inhibitors, antihistaminic drugs, forskolinpreparations, phosphodiesterase inhibitors, cannabinoid-2 receptorstimulants and the like.

Examples of the immunosuppressants include azathioprine (trade name:IMULAN and AZANIN), mizoribine (trade name: BREDININ), methotrexate(trade name: METHOTREXATE, RHEUMATREX), mycophenolate mofetil (tradename: CELLCEPT), cyclophosphamide (trade name: ENDOXAN P), ciclosporin A(trade name: NEORAL, SANDIMMUN), tacrolimus (FK506, trade name:PROGRAF), sirolimus (RAPAMYCIN), everolimus (trade name: CERTICAN),prednisolone (trade name: PREDONIN), methylprednisolone (trade name:MEDROL), orthoclone OKT3 (trade name: MUROMONAB CD3), anti humanlymphocyte globulin (ALG, trade name: ALBULIN), deoxyspergualin (DSG,gusperimus hydrochloride, trade name: SPANIDIN) and the like.

Examples of antibiotics include cefuroxime sodium, meropenem trihydrate,netilmicin sulfate, sisomicin sulfate, ceftibuten, PA-1806, IB-367,tobramycin, PA-1420; doxorubicin, astromicin sulfate, or cefetametpivoxil hydrochloride, etc.

Examples of antibiotics as an inhalant include PA-1806, IB-367,tobramycin, PA-1420, doxorubicin, astromicin sulfate, or cefetametpivoxil hydrochloride, etc.

Regarding the steroid, in the case of external preparations, examplesinclude clobetasol propionate, diflorasone diacetate, fluocinonide,mometasone furancarboxylate, betamethasone dipropionate, betamethasonebutyrate propionate, betamethasone valerate, difluprednate, budesonide,diflucortolone valerate, amcinonide, halcinonide, dexamethasone,dexamethasone propianate, dexamethasone valerate, dexamethasone acetate,hydrocortisone acetate, hydrocortisone butyrate, hydrocortisone butyratepropionate, deprodone propionate, prednisolone valerate acetate,fluocinolone acetonide, beclometasone propionate, triamcinoloneacetonide, flumetasone pivalate, alclometasone dipropionate, clobetasonebutyrate, prednisolone, beclomethasone dipropionate, fludroxycortide andthe like. Examples of internal medicines and injections includecortisone acetate, hydrocortisone, hydrocortisone sodium phosphate,hydrocortisone sodium succinate, fludrocortisone acetate, prednisolone,prednisolone acetate, prednisolone sodium succinate, prednisolonebutylacetate, prednisolone sodium phosphate, halopredone acetate,methylprednisolone, methylprednisolone acetate, methylprednisolonesodium succinate, triamcinolone, triamcinolone diacetate, triamcinoloneacetonide, dexamethasone, dexamethasone acetate, dexamethasone sodiumphosphate, dexamethasone palmitate, paramethasone acetate, betamethasoneand the like. Examples of inhalations include beclometasonedipropionate, fluticasone propionate, budesonide, flunisolide,triamcinolone, ST-126P, ciclesonide, dexamethasone palmitate, mometasonefuroate, sodium prasterone sulfate, deflazacort, methylprednisolonesuleptanate, methylprednisolone sodium succinate and the like.

Examples of the nonsteroidal antiinflammatory drug (NSAID) includesasapyrine, sodium salicylate, aspirin, aspirin dialuminate formulation,diflunisal, indomethacin, suprofen, ufenamate, dimethylisopropyl azulen,bufexamac, felbinac, diclofenac, tolmetin sodium, Clinoril, fenbufen,napmetone, proglumetacin, indomethacin farnesil, acemetacin,proglumetacin maleate, amfenac sodium, mofezolac, etodolac, ibuprofen,ibuprofen piconol, naproxen, flurbiprofen, flurbiprofen axethyl,ketoprofen, fenoprofen calcium, tiaprofenen, oxaprozin, pranoprofen,loxoprofen sodium, aluminoprofen, zaltoprofen, mefenamic acid, aluminummefenamate, tolfenamic acid, floctafenine, ketophenylbutazone,oxyfenbutazone, piroxicam, tenoxicam, anpiroxicam, napageln cream,epirizole, tiaramide hydrochloride, tinoridine hydrochloride,emorfazone, sulpyrine, Migrenin, Saridon, Sedes G Amipylo N, Sorbon,pyrine system antipyretics, acetaminophen, phenacetin, dimethothiazinemesylate, simetride formulation, and antipyrine system antipyretics,etc.

Examples of the disease modifying anti-rheumatic drug (DMARDs,slow-acting anti-rheumatic drug) include, for example, gold thioglucose,aurothiomalate sodium, auranofin, actarit, D-penicillamine preparations,lobenzarit disodium, bucillamine, hydroxychloroquine,salazosulfapyridine, methotrexate, and leflunomide, etc.

Examples of the antiinflammatory enzyme preparations include, forexample, lysozyme chloride, bromelain, pronase, serrapeptase, orstreptokinase-streptodornase, etc.

Examples of the chondroprotective agents include, for example,hyaluronate sodium, glucosamine, chondroitin sulfate, andglucosaminoglycan polysulfate, etc.

Examples of the prostaglandins (hereinafter referred to as “PG”) includePG receptor agonist, and PG receptor antagonist, etc. Examples of the PGreceptor include PGE receptor (EP1, EP2, EP3, EP4), PGD receptor (DP,CRTH2), PGF receptor (FP), PGI receptor (IP), or TX receptor (TP), etc.

Examples of the prostaglandin synthase inhibitor include, for example,salazosulfapyridine, mesalazine, olsalazine, 4-aminosalicylic acid,JTE-522, auranofin, carprofen, diphenpyramid, flunoxaprofen,flurbiprofen, indomethacin, ketoprofen, lornoxicam, loxoprofen,Meloxicam, oxaprozin, parsalmide, piproxen, piroxicam, piroxicambetadex, piroxicam cinnamate, tropine indomethacinate, zaltoprofen, andpranoprofen, etc.

Examples of IL-1 inhibitor (including protein preparation such as humanIL-1 receptor antagonist) include, for example, anakinra, etc.

Examples of IL-6 inhibitor (including protein preparation such asanti-IL-6 receptor antibody) include, for example, MRA, etc.

Examples of the TNF-α inhibitors (including a protein preparation suchas anti-TNF-α antibody) include, for example, infliximab, adalimumab,etanercept, etc.

Examples of the phosphodiesterase inhibitor include, for example,rolipram, cilomilast (trade name: Ariflo), Bay 19-8004, NIK-616,roflumilast (BY-217), cipamfylline (BGL-61063), atizolam (CP-80633),SCH-351591, YM-976, V-11294A, PD-168787, D-4386, IC-485, or ONO-6126 asPDE-4 inhibitor, etc.

Examples of the mediator releasing inhibitor include tranilast, sodiumcromoglicate, anlexanox, repirinast, ibudilast, tazanolast, andpemilolast sodium, etc.

Examples of the antihistamines include ketotifen fumarate, mequitazine,azelastine hydrochloride, oxatomide, terfenadine, emedastine fumarate,epinastine hydrochloride, astemizole, ebastin, cetirizine hydrochloride,bepotastine, fexofenadine, lolatadine, deslolatadine, olopatadinehydrochloride, TAK-427, ZCR-2060, NIP-530, mometasone furoate,mizolastine, BP-294, andolast, auranofin, and acribastin, etc.

Toxicity:

The present invention compounds have low toxicities and, therefore, theyare considered as sufficiently safe when used as drugs.

Effect of the Present Invention

The compounds having an ability to bind to an S1P receptor (inparticular, EDG-6, preferably EDG-1 and EDG-6) are useful asimmunosuppressants.

The present invention compounds represented by formula (I), saltsthereof, solvates thereof or prodrugs thereof are compounds having anability to bind to EDG-6 and exhibit prolonged pharmacological action.Therefore, they are useful as preventives and/or remedies in mammals, inparticular, humans for rejection in transplantation, rejection of atransplanted organ, transplantation versus host disease, autoimmunediseases (systemic lupus erythematosus, rheumatoid arthritis, myastheniagravis and the like), allergic diseases (atopic dermatitis, asthma andthe like), inflammation, infection, ulcer, lymphoma, malignant tumor,leukemia, arteriosclerosis, diseases associated with lymphocyteinfiltration into a tissue and the like.

In addition to the ability to bind to EDG-6, some of the presentinvention compounds have an agonistic activity against EDG-1 and,therefore, show an immunosuppressant effect and prolongedpharmacological action. Owing to these characteristics, they are moreuseful as preventives and/or remedies for rejection in transplantation,transplantation versus host disease, autoimmune diseases, allergicdiseases and the like.

BEST MODE FOR CARRYING OUT THE PRESENT INVENTION

The present invention will be described in greater detail by thefollowing Examples. However, the present invention is not construed asbeing restricted thereto. Concerning chromatographic separation or TLC,a solvent in parentheses corresponds to an eluting solvent or adeveloping solvent employed and a ratio is expressed in volume. Aqueousammonia used in TLC is a commercially available 28% aqueous ammonia.Concerning NMR, a solvent in parentheses corresponds to a solvent forthe measurement. Unless otherwise noted, MS was performed by using theESI (electrospray ionization) method and only cationic ions (pos.) weredetected.

The nomenclature the compounds in the present invention, was carried outby a computerized system to denominate a compound generally according toIUPAC nomenclature system such as ACD/Name (registered trade name,manufactured by Advanced Chemistry Development Inc.) or ACD/Name Batch(registered trade name, manufactured by Advanced Chemistry DevelopmentInc.), or according to IUPAC nomenclature system.

Example 1 methyl 3-[4-(3-phenylpropoxy)phenyl]propanoate

To a solution of methyl 3-(4-hydroxyphenyl)propanoate (2.50 g) and3-phenylpropan-1-ol (2.8 mL) in tetrahydrofuran (70 mL),triphenylphosphine (5.46 g) was added at room temperature. Next, diethylazodicarboxylate (9.4 mL, 40% toluene solution) was added dropwisethereto, followed by stirring at room temperature for 2 hours. Then, thereaction mixture was concentrated and the obtained residue was purifiedby silica gel column chromatography (hexane:ethyl acetate=30:1 to 5:1)to give the title compound (3.02 g) having the following physicalproperties.

TLC: Rf 0.45 (hexane:ethyl acetate=5:1);

¹H-NMR (CDCl₃): δ 2.09 (m, 2H), 2.60 (t, 2H), 2.80 (m, 2H), 2.89 (t,2H), 3.67 (s, 3H), 3.94 (t, 2H), 6.82 (d, 2H), 7.10 (d, 2H), 7.20 (m,3H), 7.29 (m, 2H).

Example 2 3-[4-(3-phenylpropoxy)phenyl]propanal

To a solution of the compound (1.0 g) prepared in Example 1 in drydichloromethane (15 mL), diisobutylaluminum hydride (3.5 mL; 0.95 Mn-hexane solution) was dropped at −78° C. and the mixture was stirred at−78° C. for 30 minutes. To the reaction mixture, methanol (0.5 mL) wasdropped, followed by stirring at room temperature for 40 minutes. Thereaction mixture was filtered through Celite (trade name) and thefiltrate was concentrated. Then, the obtained residue was purified bysilica gel column chromatography (hexane:ethyl acetate=10:1 to 6:1) togive the title compound (614 mg) having the following physicalproperties.

TLC: Rf 0.20 (hexane:ethyl acetate=7:1);

¹H-NMR (CDCl₃): δ 2.09 (m, 2H), 2.77 (m, 4H), 2.90 (t, 2H), 3.94 (t,2H), 6.82 (d, 2H), 7.09 (d, 2H), 7.20 (m, 3H), 7.27 (m, 2H), 9.82 (t,1H).

Example 3 N-{3-[4-(3-phenylpropoxy)phenyl]propyl}alanine

To a suspension of alanine (7.1 mg) in methanol (0.30 mL), sodiumhydroxide (3.4 mg) was added at room temperature. Then, the compound (30mg) prepared in Example 2 was added and the mixture was stirred at roomtemperature for 15 minutes. To the reaction mixture, sodium borohydride(4.0 mg) was added at 0° C. and the mixture was stirred at 0° C. for anhour. The reaction mixture was purified by silica gel columnchromatography (chloroform:methanol:aqueous ammonia=80:20:4) to give thetitle compound (14 mg) having the following physical properties.

TLC: Rf 0.24 (chloroform:methanol:aqueous ammonia=80:20:4);

¹H-NMR (DMSO-d₆): δ 1.23 (d, 3H), 1.81 (m, 2H), 1.98 (m, 2H), 2.53 (m,2H), 2.72 (m, 4H), 3.14 (q, 1H), 3.91 (t, 2H), 6.83 (d, 2H), 7.09 (d,2H), 7.23 (m, 5H).

Examples 3(1) to 3(38)

The procedure of Example 3 was similarly carried out, except for using acorresponding amine compound as a substitute for alanine while using thecompound prepared in Example 2 or a corresponding aldehyde compound as asubstitute therefor, followed by the conversion into a correspondingsalt by a known method, if necessary. Thus, the following compounds wereobtained.

Example 3(1) N-{3-[4-(3-phenylpropoxy)phenyl]propyl}glycine

TLC: Rf 0.52 (ethyl acetate:acetic acid:water=3:1:1);

¹H-NMR (CD₃OD): δ 2.03 (m, 4H), 2.64 (t, 2H), 2.78 (m, 2H), 2.96 (m,2H), 3.45 (s, 2H), 3.92 (t, 2H), 6.83 (d, 2H), 7.18 (m, 7H).

Example 3(2) 4-({3-[4-(3-phenylpropoxy)phenyl]propyl}amino)butanoic acid

TLC: Rf 0.25 (chloroform:methanol:aqueous ammonia=80:20:4);

¹H-NMR (CD₃OD): δ 1.83 (m, 2H), 1.94 (m, 2H), 2.04 (m, 2H), 2.37 (m,2H), 2.65 (t, 2H), 2.78 (m, 2H), 2.93 (m, 2H), 3.00 (m, 2H), 3.92 (t,2H), 6.83 (d, 2H), 7.19 (m, 7H).

Example 3(3) 5-({3-[4-(3-phenylpropoxy)phenyl]propyl}amino)pentanoicacid

TLC: Rf 0.28 (chloroform:methanol:aqueous ammonia=80:20:4);

¹H-NMR (CD₃OD): δ 1.66 (m, 4H), 2.03 (m, 4H), 2.21 (t, 2H), 2.65 (t,2H), 2.78 (m, 2H), 2.94 (m, 4H), 3.92 (t, 2H), 6.83 (d, 2H), 7.18 (m,7H).

Example 3(4) 2-methyl-N-{3-[4-(3-phenylpropoxy)phenyl]propyl}alanine

TLC: Rf 0.36 (chloroform:methanol:aqueous ammonia=80:20:4);

¹H-NMR (CDCl₃: CD₃OD=5:1): δ 1.34 (s, 6H), 1.89 (m, 2H), 2.03 (m, 2H),2.57 (m, 2H), 2.73 (m, 4H), 3.87 (t, 2H), 6.76 (d, 2H), 7.01 (d, 2H),7.13 (m, 3H), 7.20 (m, 2H).

Example 3(5) N-{3-[4-(3-phenylpropoxy)phenyl]propyl}valine

TLC: Rf 0.42 (chloroform:methanol:aqueous ammonia=80:20:4);

¹H-NMR (CDCl₃: CD₃OD=5:1): δ 0.94 (m, 6H), 1.89 (m, 2H), 2.01 (m, 2H),2.12 (m, 1H), 2.54 (m, 2H), 2.72 (m, 4H), 3.13 (d, 1H), 3.86 (t, 2H),6.75 (d, 2H), 6.99 (d, 2H), 7.12 (m, 3H), 7.20 (m, 2H).

Example 3(6) N-{3-[4-(3-phenylpropoxy)phenyl]propyl}phenylalanine

TLC: Rf 0.41 (chloroform:methanol:aqueous ammonia=80:20:4);

¹H-NMR (CDCl₃:CD₃OD=5:1): δ 1.72 (m, 2H), 2.02 (m, 2H), 2.41 (m, 2H),2.62 (m, 4H), 2.87 (m, 1H), 3.20 (m, 1H), 3.46 (m, 1H), 3.88 (m, 2H),6.71 (d, 2H), 6.89 (d, 2H) 7.16 (m, 10H).

Example 3(7) N-{3-[4-(3-phenylpropoxy)phenyl]propyl}serine

TLC: Rf 0.12 (chloroform:methanol:aqueous ammonia=80:20:4);

¹H-NMR (CDCl₃:CD₃OD=5:1): δ 2.10 (m, 4H), 2.67 (m, 2H), 2.81 (t, 2H),3.01 (m, 2H), 3.44 (t, 1H), 3.93 (m, 4H), 6.84 (d, 2H), 7.10 (d, 2H),7.22 (m, 3H), 7.29 (m, 2H).

Example 3(8) N-{3-[4-(3-phenylpropoxy)phenyl]propyl}homoserine

TLC: Rf 0.18 (chloroform:methanol:aqueous ammonia=80:20:4);

¹H-NMR (CDCl₃:CD₃OD=5:1): δ 1.99 (m, 6H), 2.57 (t, 2H), 2.73 (m, 2H),2.91 (m, 2H), 3.43 (m, 1H), 3.72 (m, 2H), 3.87 (t, 2H), 6.76 (d, 2H),7.01 (d, 2H), 7.12 (m, 3H), 7.20 (m, 2H).

Example 3(9)2-hydroxy-3-({3-[4-(3-phenylpropoxy)phenyl]propyl}amino)propanoic acid

TLC: Rf 0.12 (chloroform:methanol:aqueous ammonia=80:20:4);

¹H-NMR (CDCl₃:CD₃OD=5:1): δ 2.06 (m, 4H), 2.65 (t, 2H), 2.81 (m, 2H),2.97 (m, 3H), 3.25 (m, 1H), 3.97 (m, 2H), 4.03 (t, 1H), 6.84 (d, 2H),7.09 (d, 2H), 7.22 (m, 3H), 7.29 (m, 2H).

Example 3(10) 2-methyl-N-{3-[4-(3-phenylpropoxy)phenyl]propyl}serine

TLC: Rf 0.22 (chloroform:methanol:aqueous ammonia=80:20:4);

¹H-NMR (CDCl₃:CD₃OD=5:1): δ 1.34 (s, 3H), 2.07 (m, 4H), 2.67 (t, 2H),2.81 (m, 2H), 2.92 (m, 2H), 3.54 (d, 1H), 3.94 (m, 3H), 6.84 (d, 2H),7.10 (d, 2H), 7.21 (m, 3H), 7.29 (m, 2H).

Example 3(11) N-{[6-(3-phenylpropoxy)-2-naphthyl]methyl}glycine

TLC: Rf 0.13 (chloroform:methanol:aqueous ammonia=80:20:4);

¹H-NMR (CDCl₃:CD₃OD=5:1): δ 2.19 (m, 2H), 2.87 (t, 2H), 3.43 (s, 2H),4.10 (t, 2H), 4.22 (s, 2H), 7.12 (d, 1H), 7.27 (m, 6H), 7.44 (dd, 1H),7.77 (d, 2H), 7.82 (d, 1H).

Example 3(12) 4-({[6-(3-phenylpropoxy)-2-naphthyl]methyl}amino)butanoicacid

TLC: Rf 0.17 (chloroform:methanol:aqueous ammonia=80:20:4);

¹H-NMR (CDCl₃:CD₃OD=5:1): δ 1.84 (m, 2H), 2.18 (m, 2H), 2.44 (m, 2H),2.86 (m, 2H), 2.97 (m, 2H), 4.09 (t, 2H), 4.13 (s, 2H), 7.11 (d, 1H),7.27 (m, 6H), 7.43 (dd, 1H), 7.76 (m, 3H).

Example 3(13)2-hydroxy-3-({[6-(3-phenylpropoxy)-2-naphthyl]methyl}amino)propanoicacid

TLC: Rf 0.11 (chloroform:methanol:aqueous ammonia=80:20:4);

¹H-NMR (CDCl₃:CD₃OD=5:1): δ 2.19 (m, 2H), 2.87 (m, 2H), 3.11 (dd, 1H),3.20 (dd, 1H), 4.09 (m, 3H), 4.23 (d, 1H), 4.29 (d, 1H), 7.12 (d, 1H),7.27 (m, 6H), 7.44 (dd, 1H), 7.77 (d, 2H), 7.82 (s, 1H).

Example 3(14)N-{(2E)-3-[4-(3-phenylpropoxy)phenyl]prop-2-enyl}-β-alanine

TLC: Rf 0.13 (chloroform:methanol:aqueous ammonia=80:20:4);

¹H-NMR (CD₃OD): δ 2.07 (m, 2H), 2.49 (t, 2H), 2.79 (t, 2H), 3.16 (t,2H), 3.76 (dd, 2H), 3.96 (t, 2H), 6.12 (dt, 1H), 6.78 (d, 1H), 6.88 (d,2H), 7.20 (m, 5H), 7.39 (d, 2H).

Example 3(15)1-{3-[4-(3-phenylpropoxy)phenyl]propyl}azetidine-3-carboxylic acidacetate

TLC: Rf 0.44 (ethyl acetate:acetic acid:water=3:1:1);

¹H-NMR (CD₃OD): δ 1.71-1.92 (m, 2H), 1.98 (s, 3H), 1.99-2.12 (m, 2H),2.61 (t, 2H), 2.78 (t, 2H), 3.09-3.20 (m, 2H), 3.32-3.46 (m, 1H), 3.92(t, 2H), 4.09-4.26 (m, 4H), 6.79-6.88 (m, 2H), 7.07-7.13 (m, 2H),7.14-7.29 (m, 5H).

Example 3(16) 1-{3-[4-(3-phenylpropoxy)phenyl]propyl}proline

TLC: Rf 0.46 (ethyl acetate:acetic acid:water=3:1:1);

¹H-NMR (CD₃OD): δ 1.82-2.19 (m, 7H), 2.32-2.48 (m, 1H), 2.64 (t, 2H),2.78 (t, 2H), 2.96-3.16 (m, 2H), 3.15-3.29 (m, 1H), 3.61-3.77 (m, 1H),3.80 (dd, 1H), 3.91 (t, 2H), 6.76-6.90 (m, 2H), 7.07-7.13 (m, 2H),7.14-7.35 (m, 5H).

Example 3(17)1-{3-[4-(3-phenylpropoxy)phenyl]propyl}pyrrolidine-3-carboxylic acid

TLC: Rf 0.46 (ethyl acetate:acetic acid:water=3:1:1);

¹H-NMR (CD₃OD): δ 1.92-2.12 (m, 4H), 2.13-2.38 (m, 2H), 2.64 (t, 2H),2.78 (t, 2H), 2.98-3.09 (m, 1H), 3.10-3.20 (m, 2H), 3.22-3.47 (m, 3H),3.52-3.65 (m, 1H), 3.92 (t, 2H), 6.84 (d, 2H), 7.12 (d, 2H), 7.16-7.33(m, 5H).

Example 3(18)1-{3-[4-(3-phenylpropoxy)phenyl]propyl}piperidine-2-carboxylic acid

TLC: Rf 0.51 (ethyl acetate:acetic acid:water=3:1:1);

¹H-NMR (CD₃OD): δ 1.44-1.64 (m, 1H), 1.65-1.91 (m, 4H), 1.97-2.12 (m,4H), 2.12-2.27 (m, 1H), 2.49-2.70 (m, 2H), 2.78 (t, 2H), 2.83-3.06 (m,2H), 3.16-3.29 (m, 1H), 3.34-3.47 (m, 1H), 3.47-3.62 (m, 1H), 3.92 (t,2H), 6.77-6.87 (m, 2H), 7.08-7.14 (m, 2H), 7.14-7.31 (m, 5H).

Example 3(19)1-{3-[4-(3-phenylpropoxy)phenyl]propyl}piperidine-3-carboxylic acid

TLC: Rf 0.44 (ethyl acetate:acetic acid:water=3:1:1);

¹H-NMR (CD₃OD): δ 1.66-1.99 (m, 4H), 1.99-2.15 (m, 4H), 2.57-2.71 (m,3H), 2.78 (t, 2H), 2.88-3.39 (m, 6H), 3.92 (t, 2H), 6.77-6.89 (m, 2H),7.10-7.17 (m, 2H), 7.16-7.31 (m, 5H).

Example 3(20)1-{3-[4-(3-phenylpropoxy)phenyl]propyl}piperidine-4-carboxylic acid

TLC: Rf 0.51 (ethyl acetate:acetic acid:water=3:1:1);

¹H-NMR (CD₃OD): δ 1.78-2.15 (m, 8H), 2.31-2.47 (m, 1H), 2.63 (t, 2H),2.78 (t, 2H), 2.88-3.08 (m, 4H), 3.34-3.50 (m, 2H), 3.92 (t, 2H),6.79-6.88 (m, 2H), 7.09-7.15 (m, 2H), 7.14-7.31 (m, 5H).

Example 3(21) N-{[6-(3-phenylpropoxy)-2-naphthyl]methyl}-β-alanine

TLC: Rf 0.13 (chloroform:methanol:aqueous ammonia=80:20:4);

¹H-NMR (CDC₃): δ 2.14-2.24 (m, 2H), 2.47 (t, 2H), 2.87 (t, 2H), 3.09 (t,2H), 4.10 (t, 2H), 4.23 (s, 2H), 7.12 (d, 1H), 7.18-7.33 (m, 6H), 7.43(dd, 1H), 7.75-7.82 (m, 3H).

Example 3(22) N-{[6-(3-phenylpropoxy)-2-naphthyl]methyl}-β-alaninehydrochloride

TLC: Rf 0.13 (chloroform:methanol:aqueous ammonia=80:20:4);

¹H-NMR (CD₃OD): δ 2.09-2.19 (m, 2H), 2.76 (t, 2H), 2.84 (t, 2H),3.30-3.34 (m, 2H), 4.09 (t, 2H), 4.36 (s, 2H), 7.13-7.29 (m, 7H), 7.50(dd, 1H), 7.79-7.86 (m, 2H), 7.91 (s, 1H).

Example 3(23)1-{[6-(3-phenylpropoxy)-2-naphthyl]methyl}azetidine-3-carboxylic acidhydrochloride

TLC: Rf 0.20 (chloroform:methanol:aqueous ammonia=80:20:4);

¹H-NMR (CD₃OD): δ 2.09-2.19 (m, 2H), 2.84 (t, 2H), 3.64-3.76 (m, 1H),4.09 (t, 2H), 4.28-4.38 (m, 4H), 4.52 (s, 2H), 7.13-7.29 (m, 7H), 7.45(dd, 1H), 7.81-7.85 (m, 2H), 7.90 (s, 1H).

Example 3(24)1-{[6-(3-phenylpropoxy)-2-naphthyl]methyl}piperidine-4-carboxylic acidhydrochloride

TLC: Rf 0.21 (chloroform:methanol:aqueous ammonia=80:20:4);

¹H-NMR (CD₃OD): δ 1.75-1.93 (m, 2H), 2.09-2.27 (m, 4H), 2.56-2.65 (m,1H), 2.84 (t, 2H), 3.03-3.14 (m, 2H), 3.53-3.61 (m, 2H), 4.10 (t, 2H),4.43 (s, 2H), 7.13-7.29 (m, 7H), 7.50 (dd, 1H), 7.81-7.87 (m, 2H), 7.93(s, 1H).

Example 3(25)N-{(2E)-3-[2-methyl-4-(3-phenylpropoxy)phenyl]prop-2-enyl}-β-alaninehydrochloride

TLC: Rf 0.21 (chloroform:methanol:aqueous ammonia=80:20:4);

¹H-NMR (CD₃OD): δ 1.99-2.12 (m, 2H), 2.34 (s, 3H), 2.74-2.81 (m, 4H),3.27-3.31 (m, 2H), 3.83 (d, 2H), 3.95 (t, 2H), 6.02 (dt, 1H), 6.71-6.76(m, 2H), 7.07 (d, 1H), 7.12-7.29 (m, 5H), 7.44 (d, 1H).

Example 3(26)N-((2E)-3-{2-methyl-4-[(5-phenylpentyl)oxy]phenyl}prop-2-enyl)-β-alaninehydrochloride

TLC: Rf 0.21 (chloroform:methanol:aqueous ammonia=80:20:4);

¹H-NMR (CD₃OD): δ 1.44-1.55 (m, 2H), 1.61-1.84 (m, 4H), 2.34 (s, 3H),2.63 (t, 2H), 2.76 (t, 2H), 3.25-3.30 (m, 2H), 3.82 (d, 2H), 3.95 (t,2H), 6.02 (dt, 1H), 6.70-6.74 (m, 2H), 7.06 (d, 1H), 7.10-7.26 (m, 5H),7.43 (d, 1H).

Example 3(27)1-{(2E)-3-[4-(3-phenylpropoxy)phenyl]-2-propenyl}piperidine-4-carboxylicacid hydrochloride

TLC: Rf 0.20 (chloroform:methanol:aqueous ammonia=80:20:4);

¹H-NMR (CD₃OD): δ 1.81-2.16 (m, 6H), 2.36-2.48 (m, 1H), 2.79 (t, 2H),2.90-3.07 (m, 2H), 3.38-3.51 (m, 2H), 3.78 (d, 2H), 3.97 (t, 2H),6.07-6.18 (m, 1H), 6.80 (d, 1H), 6.89 (d, 2H), 7.11-7.29 (m, 5H), 7.41(d, 2H).

Example 3(28)1-{(2E)-3-[4-(3-phenylpropoxy)phenyl]-2-propenyl}azetidine-3-carboxylicacid hydrochloride

TLC: Rf 0.10 (chloroform:methanol:aqueous ammonia=80:20:4);

¹H-NMR (CD₃OD): δ 2.01-2.12 (m, 2H), 2.79 (t, 2H), 3.63-3.71 (m, 1H),3.92-3.99 (m, 4H), 4.23-4.40 (m, 4H), 5.97-6.09 (m, 1H), 6.81-6.92 (m,3H), 7.11-7.28 (m, 5H), 7.40 (d, 2H).

Example 3(29)N-((2E)-3-{4-[(5-phenylpentyl)oxy]phenyl}-2-propenyl)-β-alaninehydrochloride

TLC: Rf 0.20 (chloroform:methanol:aqueous ammonia=80:20:4);

¹H-NMR (CD₃OD): δ 1.41-1.57 (m, 2H), 1.61-1.74 (m, 2H), 1.74-1.85 (m,2H), 2.63 (t, 2H), 2.76 (t, 2H), 3.25-3.33 (m, 2H), 3.80 (d, 2H), 3.97(t, 2H), 6.11 (dt, 1H), 6.81 (d, 1H), 6.88 (d, 2H), 7.08-7.30 (m, 5H),7.39 (d, 2H).

Example 3(30) N-({6-[(5-phenylpentyl)oxy]-2-naphthyl}methyl)-β-alaninehydrochloride

TLC: Rf 0.17 (chloroform:methanol:aqueous ammonia=80:20:4);

¹H-NMR (CD₃OD): δ 1.48-1.63 (m, 2H), 1.64-1.79 (m, 2H), 1.80-1.94 (m,2H), 2.65 (t, 2H), 2.76 (t, 2H), 3.18-3.42 (m, 2H), 4.10 (t, 2H), 4.35(s, 2H), 7.07-7.29 (m, 7H), 7.50 (dd, 1H), 7.80 (d, 1H), 7.85 (d, 1H),7.88-7.93 (m, 1H).

Example 3(31)1-({6-[(5-phenylpentyl)oxy]-2-naphthyl}methyl)azetidine-3-carboxylicacid hydrochloride

TLC: Rf 0.14 (chloroform:methanol:aqueous ammonia=80:20:4);

¹H-NMR (CD₃OD): δ 1.46-1.64 (m, 2H), 1.64-1.79 (m, 2H), 1.79-1.95 (m,2H), 2.65 (t, 2H), 3.58-3.76 (m, 1H), 4.09 (t, 2H), 4.26-4.39 (m, 4H),4.51 (s, 2H), 7.06-7.29 (m, 7H), 7.45 (dd, 1H), 7.81 (d, 1H), 7.85 (d,1H), 7.88-7.92 (m, 1H).

Example 3(32)1-({6-[(5-phenylpentyl)oxy]-2-naphthyl}methyl)piperidine-4-carboxylicacid hydrochloride

TLC: Rf 0.16 (chloroform:methanol:aqueous ammonia=80:20:4);

¹H-NMR (CD₃OD): δ 1.46-1.64 (m, 2H), 1.63-1.79 (m, 2H), 1.79-1.97 (m,4H), 2.10-2.32 (m, 2H), 2.55-2.74 (m, 1H), 2.65 (t, 2H), 2.98-3.23 (m,2H), 3.45-3.65 (m, 2H), 4.10 (t, 2H), 4.43 (s, 2H), 7.07-7.30 (m, 7H),7.50 (dd, 1H), 7.82 (d, 1H), 7.87 (d, 1H), 7.90-7.97 (m, 1H).

Example 3(33) N-{[6-(4-phenylbutoxy)-2-naphthyl]methyl}-β-alaninehydrochloride

TLC: Rf 0.17 (chloroform:methanol:aqueous ammonia=80:20:4);

¹H-NMR (CD₃OD): δ 1.78-1.95 (m, 4H), 2.64-2.79 (m, 4H), 3.23-3.36 (m,2H), 4.07-4.16 (m, 2H), 4.35 (s, 2H), 7.09-7.31 (m, 7H), 7.50 (dd, 1H),7.80 (d, 1H), 7.85 (d, 1H), 7.87-7.92 (m, 1H).

Example 3(34)1-{[6-(4-phenylbutoxy)-2-naphthyl]methyl}azetidine-3-carboxylic acidhydrochloride

TLC: Rf 0.13 (chloroform:methanol:aqueous ammonia=80:20:4);

¹H-NMR (CD₃OD): δ 1.79-1.94 (m, 4H), 2.64-2.77 (m, 2H), 3.65-3.77 (m,1H), 4.06-4.17 (m, 2H), 4.22-4.42 (m, 4H), 4.52 (s, 2H), 7.08-7.30 (m,7H), 7.46 (dd, 1H), 7.83 (t, 2H), 7.88-7.94 (m, 1H).

Example 3(35)1-{[6-(4-phenylbutoxy)-2-naphthyl]methyl}piperidine-4-carboxylic acidhydrochloride

TLC: Rf 0.14 (chloroform:methanol:aqueous ammonia=80:20:4).

Example 3(36)N-({6-[3-(4-chlorophenyl)propoxy]-2-naphthyl}methyl)-β-alaninehydrochloride

TLC: Rf 0.14 (chloroform:methanol:aqueous ammonia=80:20:4);

¹H-NMR (CD₃OD): δ 2.03-2.24 (m, 2H), 2.76 (t, 2H), 2.84 (t, 2H),3.25-3.36 (m, 2H), 4.09 (t, 2H), 4.36 (s, 2H), 7.16-7.30 (m, 6H), 7.50(dd, 1H), 7.83 (t, 2H), 7.88-7.94 (m, 1H).

Example 3(37)1-({6-[3-(4-chlorophenyl)propoxy]-2-naphthyl}methyl)azetidine-3-carboxylicacid hydrochloride

TLC: Rf 0.11 (chloroform:methanol:aqueous ammonia=80:20:4);

¹H-NMR (CD₃OD): δ 2.05-2.21 (m, 2H), 2.84 (t, 2H), 3.60-3.79 (m, 1H),4.09 (t, 2H), 4.24-4.40 (m, 4H), 4.52 (s, 2H), 7.17-7.31 (m, 6H), 7.46(dd, 1H), 7.79-7.87 (m, 2H), 7.88-7.94 (m, 1H).

Example 3(38)1-({6-[3-(4-chlorophenyl)propoxy]-2-naphthyl}methyl)piperidine-4-carboxylicacid hydrochloride

TLC: Rf 0.15 (chloroform:methanol:aqueous ammonia=80:20:4);

¹H-NMR (CD₃OD): δ 1.72-1.97 (m, 2H), 2.03-2.32 (m, 4H), 2.52-2.71 (m,1H), 2.83 (t, 2H), 2.95-3.20 (m, 2H), 3.47-3.69 (m, 2H), 4.09 (t, 2H),4.43 (s, 2H), 7.13-7.32 (m, 6H), 7.52 (dd, 1H), 7.76-7.90 (m, 2H),7.90-7.99 (m, 1H).

Example 4 tert-butyl N-[3-(4-hydroxyphenyl)propyl]-β-alaninate

To a methanol solution (25 mL) of 4-(3-aminopropyl)phenol (1.83 g),tert-butyl acrylate (1.7 mL) was added dropwise thereto at roomtemperature, followed by stirring at room temperature overnight. Thereaction mixture was concentrated. The residue was purified by silicagel column chromatography (ethyl acetate→ethyl acetate:methanol=3:1) togive the title compound (1.55 g) having the following physicalproperties.

TLC: Rf 0.24 (ethyl acetate:methanol=5:1);

¹H-NMR (CDCl₃): δ 1.45 (s, 9H), 1.79 (m, 2H), 2.44 (t, 2H), 2.60 (m,4H), 2.83 (t, 2H), 6.68 (d, 2H), 6.99 (d, 2H).

Example 5 tert-butylN-(tert-butoxycarbonyl)-N-[3-(4-hydroxyphenyl)propyl]-β-alaninate

To a tetrahydrofuran (30 mL) solution of the compound (1.55 g) preparedin Example 4, a tetrahydrofuran (3 mL) solution of di-tert-butyldicarbonate (1.15 g) was added dropwise thereto at 0° C., followed bystirring at 0° C. for 2 hours. The reaction mixture was concentrated andthe residue was purified by silica gel column chromatography(hexane:ethyl acetate=6:1 to 3:1) to give the title compound (1.57 g)having the following physical properties.

TLC: Rf 0.45 (hexane:ethyl acetate=2:1);

¹H-NMR (CDCl₃): δ 1.43 (m, 18H), 1.79 (m, 2H), 2.51 (m, 4H), 3.22 (m,2H), 3.42 (m, 2H), 4.92 (s, 1H), 6.75 (d, 2H), 7.03 (d, 2H).

Example 6 tert-butylN-(tert-butoxycarbonyl)-N-{3-[4-(3-phenylpropoxy)phenyl]propyl}-β-alaninate

To a solution of the compound (3.6 g) prepared in Example 5 indimethylformamide (36 mL), potassium carbonate (4.20 g) was added atroom temperature and (3-bromopropyl)benzene (2.31 mL) was added dropwisethereto, followed by stirring at room temperature overnight. Thereaction mixture was poured into ice-water and extracted with a mixedsolvent (hexane:ethyl acetate=2:1, twice). The organic layer wassuccessively washed with water and a saturated aqueous sodium chloridesolution, dried over anhydrous magnesium sulfate and concentrated. Theresidue was purified by silica gel column chromatography (hexane:ethylacetate=30:1 to 4:1) to give the title compound (4.44 mg) having thefollowing physical properties.

TLC: Rf 0.18 (hexane:ethyl acetate=10:1);

¹H-NMR (CDCl₃): δ 1.43 (s, 18H), 1.81 (m, 2H), 2.09 (m, 2H), 2.52 (m,4H), 2.81 (t, 2H), 3.22 (m, 2H), 3.42 (m, 2H), 3.94 (t, 2H), 6.81 (d,2H), 7.08 (d, 2H), 7.21 (m, 3H), 7.29 (m, 2H).

Example 7 N-{3-[4-(3-phenylpropoxy)phenyl]propyl}-β-alaninehydrochloride

To a solution of the compound (4.68 g) prepared in Example 6 in1,4-dioxane (9 mL), a 4N hydrogen chloride-1,4-dioxane solution (38 mL)was added at room temperature, followed by stirring at room temperatureovernight. The precipitate was collected by filtration and dried. Thus,the title compound (2.87 g) having the following physical properties wasobtained.

TLC: Rf 0.31 (chloroform:methanol:aqueous ammonia=80:20:4);

¹H-NMR (CD₃OD): δ 2.02 (m, 4H), 2.65 (t, 2H), 2.71 (t, 2H), 2.78 (t,2H), 3.01 (m, 2H), 3.24 (t, 2H), 3.92 (t, 2H), 6.84 (d, 2H), 7.12 (d,2H), 7.20 (m, 5H).

Examples 8 to 8(3)

The procedures of Examples 6 and 7 were followed but using acorresponding derivative as a substitute for (3-bromopropyl)benzene,followed by the conversion into a corresponding salt by a known method,if necessary. Thus, the following compounds were obtained.

Example 8 N-(3-({4-[3-(4-methoxyphenyl)propoxy]phenyl}propyl)-β-alaninehydrochloride

TLC: Rf 0.25 (chloroform:methanol:aqueous ammonia=80:20:4);

¹H-NMR (CD₃OD): δ 2.00 (m, 4H), 2.69 (m, 6H), 3.01 (m, 2H), 3.23 (t,2H), 3.74 (s, 3H), 3.90 (t, 2H), 6.82 (m, 4H), 7.11 (m, 4H).

Example 8(1)N-(3-{4-[3-(3,4-dimethoxyphenyl)propoxy]phenyl}propyl)-β-alanine acetate

TLC: Rf 0.25 (chloroform:methanol:aqueous ammonia=80:20:4);

¹H-NMR (CD₃OD): δ 1.90 (s, 3H), 2.02 (m, 4H), 2.47 (t, 2H), 2.64 (t,2H), 2.73 (t, 2H), 2.96 (m, 2H), 3.11 (t, 2H), 3.73 (s, 3H), 3.78 (s,3H), 3.91 (t, 2H), 6.76 (m, 2H), 6.84 (m, 3H), 7.12 (d, 2H).

Example 8(2) N-(3-{4-[3-(4-chlorophenyl)propoxy]phenyl}propyl)-β-alaninehydrochloride

TLC: Rf 0.25 (chloroform:methanol:aqueous ammonia=80:20:4);

¹H-NMR (CD₃OD): δ 2.02 (m, 4H), 2.65 (t, 2H), 2.72 (t, 2H), 2.78 (t,2H), 3.01 (m, 2H), 3.24 (t, 2H), 3.92 (t, 2H), 6.84 (d, 2H), 7.12 (d,2H), 7.18 (d, 2H), 7.25 (d, 2H).

Example 8(3)N-(3-{4-[(7-chloroquinolin-2-yl)methoxy]phenyl}propyl)-β-alaninehydrochloride

TLC: Rf 0.14 (chloroform:methanol:aqueous ammonia=80:20:4);

¹H-NMR (DMSO-d₆): δ 1.84 (m, 2H), 2.56 (t, 2H), 2.65 (t, 2H), 2.86 (m,2H), 3.08 (m, 2H), 5.34 (s, 2H), 6.99 (d, 2H), 7.14 (d, 2H), 7.66 (dd,1H), 7.69 (d, 1H), 8.06 (m, 2H), 8.47 (d, 1H), 8.66 (s, 2H).

Example 9 methylN-[2-(4-hydroxyphenyl)ethyl]-N-(trifluoroacetyl)-β-alaninate

To a solution of tyramine (3.0 g) in methanol (40 mL), acrylate (0.98mL) in methanol (5.0 mL) was dropped at room temperature, followed bystirring at room temperature for 13 hours. Then, the mixture wasconcentrated and azeotropically distilled with toluene. The residue wasdissolved in dichloromethane (30 mL) and trifluoroacetic anhydride (4.6mL) and pyridine (2.6 mL) were added at 0° C., followed by stirring atroom temperature for 2 hours. Then, chloroform (30 mL) was added to thereaction mixture. The organic layer was successively washed with asaturated aqueous ammonium chloride solution, water and 1N hydrochloricacid, dried over anhydrous magnesium sulfate and concentrated. Theresidue was purified by silica gel column chromatography(chloroform:methanol=40:1) to give the title compound (1.43 mg) havingthe following physical properties.

TLC: Rf 0.63 (chloroform:methanol:aqueous ammonia=8:1:0.1);

¹H-NMR (DMSO-d₆): δ 2.63 (t, 2H), 2.77 (t, 2H), 2.90-2.96 (m, 3H), 3.55(t, 2H), 3.59-3.68 (m, 2H), 6.71 (d, 2H), 7.01 (d, 2H), 8.83 (s, 1H).

Example 10 methylN-(2-{4-[(3-phenylprop-2-ynyl)oxy]phenyl}ethyl)-N-(trifluoroacetyl)-β-alaninate

The procedure of Example 1 was similarly carried out, except for usingthe compound prepared in Example 9 as a substitute for methyl3-(4-hydroxyphenyl)propanoate while using 3-phenylprop-2-yn-1-ol as asubstitute for 3-phenylpropan-1-ol. Thus, the title compound having thefollowing physical properties was obtained.

TLC: Rf 0.43 (hexane:ethyl acetate=3:1);

¹H-NMR (CDCl₃): δ 2.55 (t, 1.2H), 2.68 (t, 0.8H), 2.79-2.92 (m, 2H),3.51-3.70 (m, 4H), 3.67-3.70 (m, 3H), 4.90 (s, 2H), 6.93-7.04 (m, 2H),7.08-7.19 (m, 2H), 7.27-7.35 (m, 3H), 7.39-7.47 (m, 2H).

Example 11 N-(2-{4-[(3-phenylprop-2-ynyl)oxy]phenyl}ethyl)-β-alanine

To a solution of the compound (39 mg) prepared in Example 10 in amixture of tetrahydrofuran (1 mL) and methanol (0.5 mL), 1 N aqueoussodium hydroxide solution (0.5 mL) was added, followed by stirring for 3hours. Then, the reaction mixture was concentrated. The residue waspurified by silica gel column chromatography (chloroform:methanol:formicacid=15:1:0.5) to give the title compound (18 mg) having the followingphysical properties.

TLC: Rf 0.26 (chloroform:methanol:formic acid=10:1:0.5);

¹H-NMR (CD₃OD): δ 2.48 (t, 2H), 2.95 (t, 2H), 3.11-3.26 (m, 4H), 4.93(s, 2H), 7.02 (d, 2H), 7.24 (d, 2H), 7.27-7.35 (m, 3H), 7.35-7.43 (m,2H).

Examples 12 to 12(2)

The procedures of Examples 1 and 11 were followed but using acorresponding alcohol compound as a substitute for methyl3-(4-hydroxyphenyl)propanoate while using a corresponding alcoholcompound as a substitute for 3-phenylpropan-1-ol, followed by theconversion into a corresponding salt by a known method, if necessary.Thus, the following compounds were obtained.

Example 12N-[2-(4-{[(2E)-3-phenylprop-2-enyl]oxy}phenyl)ethyl]-β-alanine formate

TLC: Rf 0.28 (chloroform:methanol:formic acid=10:1:0.5);

¹H-NMR (CD₃OD): δ 2.52 (t, 2H), 2.93 (t, 2H), 3.14-3.27 (m, 4H), 4.69(dd, 2H), 6.43 (dt, 1H), 6.73 (d, 1H), 6.96 (d, 2H), 7.14-7.26 (m, 3H),7.30 (t, 2H), 7.41 (d, 2H), 8.32 (s, 1H).

Example 12(1) N-(3-{4-[(3-phenylprop-2-ynyl)oxy]phenyl}propyl)-β-alanine

TLC: Rf 0.31 (chloroform:methanol:formic acid=10:1:0.5);

¹H-NMR (CD₃OD): δ 1.89-2.05 (m, 2H), 2.58 (t, 2H), 2.67 (t, 2H),2.94-3.05 (m, 2H), 3.17 (t, 2H), 4.91 (s, 2H), 6.98 (d, 2H), 7.17 (d,2H), 7.28-7.35 (m, 3H), 7.35-7.42 (m, 2H).

Example 12(2)N-[3-(4-{[(2E)-3-phenylprop-2-enyl]oxy}phenyl)propyl]-β-alanine

TLC: Rf 0.35 (chloroform:methanol:formic acid=10:1:0.5);

¹H-NMR (CD₃OD): δ 1.83-2.06 (m, 2H), 2.51 (t, 2H), 2.67 (t, 2H),2.92-3.05 (m, 2H), 3.14 (t, 2H), 4.68 (dd, 2H), 6.43 (dt, 1H), 6.73 (d,1H), 6.92 (d, 2H), 7.15 (d, 2H), 7.19-7.26 (m, 1H), 7.27-7.34 (m, 2H),7.37-7.45 (m, 2H).

Example 13 ethyl (2E)-2-cyano-3-[4-(3-phenylpropoxy)phenyl]acrylate

4-(3-phenylpropoxy)benzaldehdye (240 mg), ethyl cyanoacetate (0.094 mL)and ammonium acetate (74 mg) were mixed and reacted under microwaveirradiation (50 W, 100° C., 10 minutes). Then, water was added to thereaction mixture, followed by extraction with ethyl acetate. The organiclayer was dried over anhydrous magnesium sulfate and concentrated. Theabove procedure was repeated thrice to give three residues. The residueswere combined and purified by silica gel column chromatography(hexane:ethyl acetate=20:1 to 7:1) to give the title compound (629 mg)having the following physical properties.

TLC: Rf 0.28 (hexane:ethyl acetate=5:1);

¹H-NMR (CDCl₃): δ 1.39 (t, 3H), 2.15 (m, 2H), 2.83 (m, 2H), 4.04 (t,2H), 4.37 (q, 2H), 6.97 (d, 2H), 7.21 (m, 3H), 7.29 (m, 2H), 7.99 (d,2H), 8.17 (s, 1H).

Example 14 ethyl 2-cyano-3-[4-(3-phenylpropoxy)phenyl]propanoate

Under an argon atmosphere, ethanol (1 mL) was added to palladium carboncontaining 10% moisture (250 mg). Next, a solution of the compound (620mg) prepared in Example 13 in a mixture of ethanol (4 mL) and ethylacetate (4 mL) was added thereto. After purging with hydrogen, themixture was stirred at room temperature for 2 hours. Then, the reactionmixture was filtered through Celite (trade name). The filtrate wasconcentrated to give the title compound (594 mg) having the followingphysical properties.

TLC: Rf 0.26 (hexane:ethyl acetate=5:1);

¹H-NMR (CDCl₃): δ 1.28 (t, 3H), 2.10 (m, 2H), 2.81 (m, 2H), 3.18 (m,2H), 3.67 (dd, 1H), 3.95 (t, 2H), 4.24 (q, 2H), 6.85 (d, 2H), 7.19 (m,5H), 7.28 (m, 2H).

Example 15 3-amino-2-[4-(3-phenylpropoxy)benzyl]propan-1-ol

To lithium aluminum hydride (131 mg) was added dry tetrahydrofuran (10mL). Then, a solution of the compound (290 mg) prepared in Example 14 indry tetrahydrofuran (15 mL) was added dropwise thereto, followed bystirring at 60° C. for 3 hours. To the reaction mixture, 1 Nhydrochloric acid was added at 0° C., followed by stirring at roomtemperature for 1 hour. Anhydrous sodium sulfate was added to thereaction mixture and the mixture was filtered through Celite (tradename). The filtrate was concentrated to give the title compound (284 mg)having the following physical properties as a crude product. Theobtained compound was used in the next reaction without furtherpurification.

TLC: Rf 0.43 (chloroform:methanol:aqueous ammonia=80:20:4).

Example 16 N-{3-hydroxy-2-[4-(3-phenylpropoxy)benzyl]propyl}-β-alanine

To a solution of tert-butylN-{3-hydroxy-2-[4-(3-phenylpropoxy)benzyl]propyl}-β-alaninate (65 mg;prepared by following the procedure of Example 4 using the compoundprepared in Example 15 as a substitute for 4-(3-aminopropyl)phenol) indichloromethane (3 mL), trifluoroacetic acid (3 mL) was dropped at 0°C., followed by stirring at room temperature for 2 hours. Then, thereaction mixture was concentrated. The residue was purified by silicagel column chromatography (chloroform:methanol:aqueous ammonia=80:20:4).The crude product thus obtained was washed with diethyl ether to givethe title compound (38 mg) having the following physical properties.

TLC: Rf 0.56 (ethyl acetate:acetic acid:water=3:1:1);

¹H-NMR (DMSO-d₆): δ 1.86 (m, 1H), 1.99 (m, 2H), 2.18 (t, 2H), 2.59 (m,1H), 2.71 (m, 3H), 2.80 (t, 2H), 3.37 (m, 4H), 3.91 (t, 2H), 6.83 (d,2H), 7.09 (d, 2H), 7.23 (m, 5H).

Example 17 cyano[4-(3-phenylpropoxy)phenyl]methyl acetate

To dry dichloromethane (3 mL), a solution of titanium tetraisopropoxide(0.074 mL) and 4-(3-phenylpropoxy)benzaldehyde (300 mg) in drydichloromethane (3 mL) and trimethylsilyl cyanide were successivelydropped, followed by stirring at room temperature overnight. To thereaction mixture, 1 N hydrochloric acid (3 mL) was added at 0° C.,followed by stirring at room temperature for 6.5 hours. After addingwater, the reaction mixture was extracted with dichloromethane. Theorganic layer was washed with a saturated aqueous sodium chloridesolution, dried over anhydrous magnesium sulfate and filtered. To thefiltrate, acetic anhydride (0.24 mL) and pyridine (0.20 mL) weresuccessively dropped at room temperature, followed by stirring at roomtemperature overnight. Then, the reaction mixture was concentrated. Theresidue was purified by silica gel column chromatography (hexane:ethylacetate=10:1) to give the title compound (160 mg) having the followingphysical properties.

TLC: Rf 0.30 (hexane:ethyl acetate=5:1);

¹H-NMR (CDCl₃): δ 2.05-2.20 (m, 5H), 2.81 (t, 2H), 3.98 (t, 2H), 6.35(s, 1H), 6.93 (d, 2H), 7.16-7.24 (m, 3H), 7.27-7.34 (m, 2H), 7.44 (d,2H).

Example 18 3-hydroxy-3-[4-(3-phenylpropoxy)phenyl]propanenitrile

To dry tetrahydrofuran (14 mL), n-butyl lithium (0.94 mL; a 1.6 M hexanesolution) and dry acetonitrile (0.082 mL) were successively dropped at−78° C. After stirring for 30 minutes, a solution of4-(3-phenylpropoxy)benzaldehyde (300 mg) in dry tetrahydrofuran (3 mL)was dropped into the mixture at −78° C. The reaction mixture was stirredat room temperature for 1 hour, then poured into ice-water and extractedwith ethyl acetate. The organic layer was successively washed with waterand a saturated aqueous sodium chloride solution, dried over anhydrousmagnesium sulfate and concentrated. The residue was washed with a mixedsolvent of diethyl ether and hexane and filtered to give the titlecompound (238 mg) having the following physical properties.

TLC: Rf 0.52 (hexane:ethyl acetate=1:1);

¹H-NMR (CDCl₃): δ 2.11 (m, 2H), 2.18 (d, 1H), 2.76 (m, 4H), 3.97 (t,2H), 5.00 (td, 1H), 6.91 (d, 2H), 7.20 (m, 3H), 7.30 (m, 4H).

Examples 19 to 19(1)

By using the compound prepared in Example 17 or 18 as a substitute forthe compound prepared in Example 14, the procedures of Example 15,Example 4 and Example 11 were followed in this order to thereby give thefollowing compounds.

Example 19 N-{2-hydroxy-2-[4-(3-phenylpropoxy)phenyl]ethyl}-β-alaninatesodium salt

TLC: Rf 0.55 (ethyl acetate:acetic acid:water=3:1:1);

¹H-NMR (CD₃OD): δ 2.00-2.10 (m, 2H), 2.38 (t, 2H), 2.68-2.90 (m, 6H),3.94 (t, 2H), 4.70 (dd, 1H), 6.86 (d, 2H), 7.12-7.28 (m, 7H).

Example 19(1)N-{(3-hydroxy-3-[4-(3-phenylpropoxy)phenyl]propyl}-β-alanine

TLC: Rf 0.48 (ethyl acetate:acetic acid:water=3:1:1);

¹H-NMR (CD₃OD): δ 1.98-2.10 (m, 4H), 2.48 (t, 2H), 2.78 (t, 2H),3.04-3.20 (m, 4H), 3.94 (t, 2H), 4.78 (t, 1H), 6.89 (d, 2H), 7.12-7.31(m, 7H).

Example 20 1-[4-(3-phenylpropoxy)phenyl]prop-2-en-1-ol

To a solution of 4-(3-phenylpropoxy)benzaldehyde (10.4 g) in drytetrahydrofuran (100 mL), a solution of bromo(vinyl) magnesium intetrahydrofuran (14%, about 1 M) was added at 0° C. After stirring for15 minutes, the reaction mixture was added to a cold saturated aqueousammonium chloride solution and extracted with ethyl acetate. The organiclayer was successively washed with water and a saturated aqueous sodiumchloride solution, dried over anhydrous magnesium sulfate andconcentrated. The residue was purified by silica gel columnchromatography (hexane:ethyl acetate=20:1 to 3:1) to give the titlecompound (10.01 g) having the following physical properties.

TLC: Rf 0.24 (hexane:ethyl acetate=4:1);

¹H-NMR (CDCl₃): δ 1.85 (d, 1H), 2.04-2.17 (m, 2H), 2.81 (t, 2H), 3.96(t, 2H), 5.14-5.21 (m, 2H), 5.34 (dt, 1H), 6.05 (ddd, 1H), 6.88 (d, 2H),7.16-7.23 (m, 3H), 7.25-7.32 (m, 4H).

Example 21 oxiran-2-yl[4-(3-phenylpropoxy)phenyl]methanol

To a solution of the compound (3.0 g) prepared in Example 20,m-chloroperbenzoic acid (7.67 g; mCPBA) was added at room temperature.After stirring for 4 hours, the reaction mixture was poured into a cold0.1 N aqueous sodium hydroxide solution and extracted with a mixedsolvent (hexane:ethyl acetate=1:5). The organic layer was successivelywashed with water and a saturated aqueous sodium chloride solution,dried over anhydrous magnesium sulfate and concentrated. The residue waspurified by silica gel column chromatography (hexane:ethyl acetate=10:1to 2:1) to give the title compound (1.96 g) having the followingphysical properties.

TLC: Rf 0.29 (hexane:ethyl acetate=2:1);

¹H-NMR (CDCl₃): δ 2.06-2.15 (m, 2H), 2.23 (d, 0.5H), 2.76-2.89 (m,3.5H), 2.98 (dd, 0.5H), 3.17-3.27 (m, 1H), 3.97 (t, 2H), 4.43 (t, 0.5H),4.89 (d, 0.5H), 6.87-6.93 (m, 2H), 7.16-7.24 (m, 3H), 7.26-7.36 (m, 4H).

Example 22N-{2,3-dihydroxy-3-[4-(3-phenylpropoxy)phenyl]propyl}-β-alanine

To a 2.5 N aqueous sodium hydroxide solution (2.2 mL) of β-alanine (550mg), a solution of the compound (350 mg) prepared in Example 21 in2-propanol (2.2 mL) was dropped, followed by stirring at 50° C. for 2hours. Then, the reaction mixture was cooled and 1 N hydrochloric acid(5.5 mL) was added thereto at 0° C., followed by concentration. Theresidue was purified by silica gel column chromatography(chloroform:methanol:aqueous ammonia=80:20:4) to give the title compound(313 mg) having the following physical properties.

TLC: Rf 0.16 (chloroform:methanol:aqueous ammonia=80:40:4);

¹H-NMR (CD₃OD): δ 2.01-2.10 (m, 2H), 2.42-2.51 (m, 2H), 2.78 (t, 2H),2.85-3.18 (m, 4H), 3.84-3.97 (m, 3H), 4.52 (d, 0.5H), 4.59 (d, 0.5H),6.88-6.92 (m, 2H), 7.11-7.26 (m, 5H), 7.26-7.34 (m, 2H).

Example 23 N-{2-hydroxy-3-[4-(3-phenylpropoxy)phenyl]propyl}-β-alanine

By using 1-allyl-4-(3-phenylpropoxy)benzene as a substitute for thecompound prepared in Example 20, the procedures of Example 21 andExample 22 were followed to thereby give the title compound having thefollowing physical properties.

TLC: Rf 0.19 (chloroform:methanol:aqueous ammonia=80:20:4);

¹H-NMR (CD300D): δ 2.00-2.10 (m, 2H), 2.46 (t, 2H), 2.66-2.90 (m, 5H),2.99-3.19 (m, 3H), 3.92 (t, 2H), 3.96-4.04 (m, 1H), 6.84 (d, 2H),7.11-7.29 (m, 7H).

Example 24N-(tert-butoxycarbonyl)-N-[3-(4-hydroxyphenyl)propyl]-β-alanine

By using 3-(4-hydroxyphenyl)propanenitrile as a substitute for thecompound prepared in Example 14, the procedures of Example 15, Example4, Example 5 and Example 11 were followed in this order to thereby givethe title compound having the following physical properties.

TLC: Rf 0.40 (hexane:ethyl acetate=1:3);

¹H-NMR (CDCl₃): δ 1.45 (s, 9H), 1.81 (m, 2H), 2.52 (t, 2H), 2.61 (t,2H), 3.22 (m, 2H), 3.47 (t, 2H), 6.76 (d, 2H), 7.02 (d, 2H).

Example 25 N-[3-(4-hydroxyphenyl)propyl]-β-alanine hydrochloride

By using the compound prepared in Example 24 as a substitute for thecompound prepared in Example 6, the procedure of Example 7 was followedto thereby give the title compound having the following physicalproperties.

TLC: Rf 0.69 (ethyl acetate:acetic acid:water=3:1:1);

¹H-NMR (CD₃OD): δ 1.95 (m, 2H), 2.62 (t, 2H), 2.72 (t, 2H), 3.00 (m,2H), 3.24 (t, 2H), 6.71 (d, 2H), 7.03 (d, 2H).

Example 26N-[2-(4-{2-[4-(benzyloxy)phenyl]ethoxy}phenyl)ethyl]-β-alaninetrifluoracete

Step A:

To a suspension of Wang resin (manufactured by Argonaut Technology; CatNo. 800296) (1.06 mmol/g, 10.6 g, 11.2 mmol) in dichloromethane (100mL), N,N-diisopropylethylamine (17.4 mL; 100 mmol) was added at −78° C.Further, acrylic acid chloride (4.06 mL; 50 mmol) was added and themixture was shaken at room temperature overnight. After aspiration ofthe solvent, the obtained resin was washed with dichloromethane 4 timesto give an acrylate resin (10.9 g).

Step B:

To the acrylate resin (1.5 g), a solution of 4-(2-aminoethyl)phenol (20mmol) in N-methylpyrrolidone (20 mL) was added at room temperature andthe mixture was shaken at room temperature overnight. After aspirationof the solvent, the obtained resin was washed with dichloromethane 4times to give an phenol resin (1.78 g, 1.2 mmol/g).

Step C:

To the phenol resin (50 mg, 0.060 mmol), 2-[4-(benzyloxy)phenyl]ethanol(0.30 mmol) was added at room temperature. Further, a mixed solvent (1mL; dichloromethane:dry tetrahydrofuran=1:1) was added, followed by theaddition of tri-n-butylphosphine (0.30 mmol) and1,1′-azobis(N,N-dimethylformamide) (0.30 mmol). Then, the mixture wasshaken at room temperature overnight. The resin was taken up byfiltration and washed successively with a mixed solvent(dichloromethane:tetrahydrofuran=1:1) 3 times, dichloromethane 3 times,methanol 4 times, a mixed solvent (dichloromethane:methanol=3:1) 2 timesand dichloromethane 3 times. Next, trifluoroacetic acid (0.5 mL) anddichloromethane (0.5 mL) were added and the mixture was shaken at roomtemperature for 4 hours. After filtering off the resin and washing withdichloromethane 4 times, the filtrate was concentrated to thereby givethe title compound having the following physical properties.

HPLC retention time (minute): 3.67; MS (m/z): 839 (2M+H)+, 420 (M+H)+.

Unless otherwise noted, HPLC was conducted under the followingconditions.

Column: Xterra (trade name) MS C₁₈ 5 μm, 4.6×50 mm I.D.Flow rate: 3 ml/minSolvent A: 0.1% aqueous solution of trifluoroacetic acidSolvent B: 0.1% solution of trifluoroacetic acid in acetonitrile

Within 0.5 minute following the initiation of the measurement, themixing rate of the solution A to the solution B was fixed to 95/5.Subsequently, the mixing ratio of the solution A to the solution B waslinearly changed to 0/100 within 2.5 minutes, and fixed to 0/100 during0.5 minute. In the subsequent 0.01 minute, the mixing rate of thesolution A to the solution B was linearly changed to 95/5.

Examples 26(1) to 26(244)

The procedure of Example 26 was similarly carried out, except for using4-(2-aminoethyl)phenol or a corresponding derivative as a substitutetherefor and 2-[4-(benzyloxy)phenyl]ethanol or a correspondingderivative as a substitute therefor to thereby give the followingcompounds.

Example 26(1) N-{2-[4-(2-phenoxyethoxy)phenyl]ethyl}-β-alaninetrifluoroacetate

HPLC retention time (minute): 3.34; MS (m/z): 659 (2M+H)⁺, 330 (M+H)⁺,266.

Example 26(2) N-{2-[4-(3-phenylpropoxy)phenyl]ethyl}-β-alaninetrifluoroacetate

HPLC retention time (minute): 3.48; MS (m/z): 655 (2M+H)⁺, 328 (M+H)⁺.

Example 26(3) N-{2-[4-(4-phenylbutoxy)phenyl]ethyl}-β-alaninetrifluoroacetate

HPLC retention time (minute): 3.58; MS (m/z): 683 (2M+H)⁺, 342 (M+H)⁺.

Example 26(4) N-(2-{4-[4-(4-methoxyphenyl)butoxy]phenyl}ethyl)-β-alaninetrifluoroacetate

HPLC retention time (minute): 3.54; MS (m/z): 743 (2M+H)⁺, 372 (M+H)⁺.

Example 26(5) N-(2-{4-[2-(benzylsulfanyl)ethoxy]phenyl}ethyl)-β-alaninetrifluoroacetate

HPLC retention time (minute): 3.48; MS (m/z): 719 (2M+H)⁺, 360 (M+H)⁺.

Example 26(6) N-{2-[4-(3-phenoxypropoxy)phenyl]ethyl}-β-alaninetrifluoroacetate

HPLC retention time (minute): 3.45; MS (m/z): 687 (2M+H)⁺, 344 (M+H)⁺.

Example 26(7) N-{2-[4-(cyclohexylmethoxy)phenyl]ethyl}-β-alaninetrifluoroacetate

HPLC retention time (minute): 3.56; MS (m/z): 611 (2M+H)⁺, 306 (M+H)⁺.

Example 26(8)N-(2-{4-[2-(2,4-difluorophenyl)ethoxy]phenyl}ethyl)-β-alaninetrifluoroacetate

HPLC retention time (minute): 3.46; MS (m/z): 699 (2M+H)⁺, 350 (M+H)⁺.

Example 26(9) N-(2-{4-[(3-phenoxybenzyl)oxy]phenyl}ethyl)-β-alaninetrifluoroacetate

HPLC retention time (minute): 3.62; MS (m/z): 783 (2M+H)⁺, 392 (M+H)⁺.

Example 26(10) N-{2-[4-(2-cyclohexylethoxy)phenyl]ethyl}-β-alaninetrifluoroacetate

HPLC retention time (minute): 3.64; MS (m/z): 639 (2M+H)⁺, 320 (M+H)⁺.

Example 26(11) N-{2-[4-(benzyloxy)phenyl]ethyl}-β-alaninetrifluoroacetate

HPLC retention time (minute): 3.34; MS (m/z): 599 (2M+H)⁺, 300 (M+H)⁺.

Example 26(12) N-{2-[4-(2-phenylethoxy)phenyl]ethyl}-β-alaninetrifluoroacetate

HPLC retention time (minute): 3.41; MS (m/z): 627 (2M+H)⁺, 314 (M+H)⁺.

Example 26(13) N-{2-[4-(3,3-dimethylbutoxy)phenyl]ethyl}-β-alaninetrifluoroacetate

HPLC retention time (minute): 3.51; MS (m/z): 587 (2M+H)⁺, 294 (M+H)⁺.

Example 26(14) N-{2-[4-(3-cyclohexylpropoxy)phenyl]ethyl}-β-alaninetrifluoroacetate

HPLC retention time (minute): 3.77; MS (m/z): 667 (2M+H)⁺, 334 (M+H)⁺.

Example 26(15) N-(2-{4-[(4-tert-butylbenzyl)oxy]phenyl}ethyl)-β-alaninetrifluoroacetate

HPLC retention time (minute): 3.50; MS (m/z): 711 (2M+H)⁺, 356 (M+H)⁺.

Example 26(16) N-(2-{4-[(4-cyclohexylbenzyl)oxy]phenyl}ethyl)-β-alaninetrifluoroacetate

HPLC retention time (minute): 3.65; MS (m/z): 763 (2M+H)⁺, 382 (M+H)⁺.

Example 26(17) N-{3-[4-(2-phenylethoxy)phenyl]propyl}-β-alaninetrifluoroacetate

HPLC retention time (minute): 3.39; MS (m/z): 655 (2M+H)⁺, 328 (M+H)⁺.

Example 26(18)N-(3-{4-[2-(2-methylphenyl)ethoxy]phenyl}propyl)-β-alaninetrifluoroacetate

HPLC retention time (minute): 3.46; MS (m/z): 683 (2M+H)⁺, 342 (M+H)⁺.

Example 26(19)N-(3-{4-[2-(3-methylphenyl)ethoxy]phenyl}propyl)-β-alaninetrifluoroacetate

HPLC retention time (minute): 3.47; MS (m/z): 683 (2M+H)⁺, 342 (M+H)⁺.

Example 26(20)N-(3-{4-[2-(4-methylphenyl)ethoxy]phenyl}propyl)-β-alaninetrifluoroacetate

HPLC retention time (minute): 3.48; MS (m/z): 683 (2M+H)⁺, 342 (M+H)⁺.

Example 26(21) N-{3-[4-(benzyloxy)phenyl]propyl}-β-alaninetrifluoroacetate

HPLC retention time (minute): 3.30; MS (m/z): 627 (2M+H)⁺, 314 (M+H)⁺.

Example 26(22) N-(4-{2-[4-(benzyloxy)phenyl]ethoxy}benzyl)-β-alaninetrifluoroacetate

HPLC retention time (minute): 3.56; MS (m/z): 406 (M+H)⁺.

Example 26(23) N-[4-(2-phenoxyethoxy)benzyl]-β-alanine trifluoroacetate

HPLC retention time (minute): 3.22; MS (m/z): 316 (M+H)⁺, 227.

Example 26(24) N-{4-[2-(benzyloxy)ethoxy]benzyl}-β-alaninetrifluoroacetate

HPLC retention time (minute): 3.21; MS (m/z): 330 (M+H)⁺, 241.

Example 26(25) N-[4-(3-phenylpropoxy)benzyl]-β-alanine trifluoroacetate

HPLC retention time (minute): 3.35; MS (m/z): 314 (M+H)⁺, 225.

Example 26(26) N-[4-(4-phenylbutoxy)benzyl]-β-alanine trifluoroacetate

HPLC retention time (minute): 3.43; MS (m/z): 328 (M+H)⁺, 239.

Example 26(27) N-{4-[(5-phenylpentyl)oxy]benzyl}-β-alaninetrifluoroacetate

HPLC retention time (minute): 3.54; MS (m/z): 342 (M+H)⁺, 253.

Example 26(28) N-[4-(2-thien-2-ylethoxy)benzyl]-β-alaninetrifluoroacetate

HPLC retention time (minute): 3.21; MS (m/z): 306 (M+H)⁺, 217.

Example 26(29) N-{4-[2-(benzylsulfanyl)ethoxy]benzyl}-β-alaninetrifluoroacetate

HPLC retention time (minute): 3.33; MS (m/z): 346 (M+H)⁺, 151.

Example 26(30) N-{4-[(6-phenylhexyl)oxy]benzyl}-β-alaninetrifluoroacetate

HPLC retention time (minute): 3.61; MS (m/z): 356 (M+H)⁺.

Example 26(31) N-{4-[3-(benzyloxy)propoxy]benzyl}-β-alaninetrifluoroacetate

HPLC retention time (minute): 3.28; MS (m/z): 344 (M+H)⁺, 255.

Example 26(32) N-{4-[(7-phenylheptyl)oxy]benzyl}-β-alaninetrifluoroacetate

HPLC retention time (minute): 3.72; MS (m/z): 370 (M+H)⁺.

Example 26(33) N-[4-(3-phenoxypropoxy)benzyl]-3-alanine trifluoroacetate

HPLC retention time (minute): 3.32; MS (m/z): 330 (M+H)⁺, 241.

Example 26(34) N-{4-[(9-phenylnonyl)oxy]benzyl}-β-alaninetrifluoroacetate

HPLC retention time (minute): 3.91; MS (m/z): 398 (M+H)⁺, 309.

Example 26(35) N-{4-[(8-phenyloctyl)oxy]benzyl}-β-alaninetrifluoroacetate

HPLC retention time (minute): 3.82; MS (m/z): 384 (M+H)⁺, 295.

Example 26(36) N-[4-(cyclohexylmethoxy)benzyl]-β-alaninetrifluoroacetate

HPLC retention time (minute): 3.41; MS (m/z): 292 (M+H)⁺, 203.

Example 26(37) N-[4-(2-cyclopentylethoxy)benzyl]-β-alaninetrifluoroacetate

HPLC retention time (minute): 3.41; MS (m/z): 292 (M+H)⁺, 203.

Example 26(38) N-(4-{[5-(benzyloxy)pentyl]oxy}benzyl)-β-alaninetrifluoroacetate

HPLC retention time (minute): 3.43; MS (m/z): 372 (M+H)⁺, 283.

Example 26(39) N-{4-[4-(benzyloxy)butoxy]benzyl}-β-alaninetrifluoroacetate

HPLC retention time (minute): 3.36; MS (m/z): 358 (M+H)⁺, 269.

Example 26(40) N-{4-[(3-phenoxybenzyl)oxy]benzyl}-β-alaninetrifluoroacetate

HPLC retention time (minute): 3.48; MS (m/z): 378 (M+H)⁺, 289.

Example 26(41) N-[4-(2-cyclohexylethoxy)benzyl]-β-alaninetrifluoroacetate

HPLC retention time (minute): 3.50; MS (m/z): 306 (M+H)⁺, 217.

Example 26(42) N-(4-butoxybenzyl)-β-alanine trifluoroacetate

HPLC retention time (minute): 3.15; MS (m/z): 252 (M+H)⁺, 163.

Example 26(43) N-[4-(cyclopentylmethoxy)benzyl]-β-alaninetrifluoroacetate

HPLC retention time (minute): 3.31; MS (m/z): 278 (M+H)⁺, 189.

Example 26(44) N-[4-(benzyloxy)benzyl]-β-alanine trifluoroacetate

HPLC retention time (minute): 3.18; MS (m/z): 286 (M+H)⁺, 197.

Example 26(45) N-[4-(2-phenylethoxy)benzyl]-β-alanine trifluoroacetate

HPLC retention time (minute): 3.26; MS (m/z): 300 (M+H)⁺, 211.

Example 26(46) N-(4-isobutoxybenzyl)-β-alanine trifluoroacetate

HPLC retention time (minute): 3.17; MS (m/z): 252 (M+H)⁺, 163.

Example 26(47) N-{4-[(4-methylpentyl)oxy]benzyl}-β-alaninetrifluoroacetate

HPLC retention time (minute): 3.38; MS (m/z): 280 (M+H)⁺, 191.

Example 26(48) N-[4-(3,3-dimethylbutoxy)benzyl]-β-alaninetrifluoroacetate

HPLC retention time (minute): 3.34; MS (m/z): 280 (M+H)⁺, 191.

Example 26(49) N-{4-[(2-propylpentyl)oxy]benzyl}-β-alaninetrifluoroacetate

HPLC retention time (minute): 3.59; MS (m/z): 308 (M+H)⁺, 219.

Example 26(50) N-[4-(3-cyclohexylpropoxy)benzyl]-β-alaninetrifluoroacetate

HPLC retention time (minute): 3.61; MS (m/z): 320 (M+H)⁺, 231.

Example 26(51) N-[4-(pentyloxy)benzyl]-β-alanine trifluoroacetate

HPLC retention time (minute): 3.29; MS (m/z): 266 (M+H)⁺, 177.

Example 26(52) N-[4-(hexyloxy)benzyl]-β-alanine trifluoroacetate

HPLC retention time (minute): 3.40; MS (m/z): 280 (M+H)⁺, 191.

Example 26(53) N-[4-(heptyloxy)benzyl]-β-alanine trifluoroacetate

HPLC retention time (minute): 3.50; MS (m/z): 294 (M+H)⁺, 205.

Example 26(54) N-[4-(octyloxy)benzyl]-β-alanine trifluoroacetate

HPLC retention time (minute): 3.62; MS (m/z): 308 (M+H)⁺, 219.

Example 26(55) N-{4-[(4-chlorobenzyl)oxy]benzyl}-β-alaninetrifluoroacetate

HPLC retention time (minute): 3.32; MS (m/z): 320 (M+H)⁺, 231.

Example 26(56)N-[3-(4-{2-[4-(benzyloxy)phenyl]ethoxy}phenyl)propyl]-β-alaninetrifluoroacetate

HPLC retention time (minute): 3.60; MS (m/z): 434 (M+H)⁺, 219.

Example 26(57) N-{3-[4-(2-phenoxyethoxy)phenyl]propyl}-β-alaninetrifluoroacetate

HPLC retention time (minute): 3.33; MS (m/z): 344 (M+H)⁺.

Example 26(58) N-(3-{4-[2-(benzyloxy)ethoxy]phenyl}propyl)-β-alaninetrifluoroacetate

HPLC retention time (minute): 3.31; MS (m/z): 358 (M+H)⁺.

Example 26(59) N-{3-[4-(3-phenylpropoxy)phenyl]propyl}-β-alaninetrifluoroacetate

HPLC retention time (minute): 3.45; MS (m/z): 342 (M+H)⁺.

Example 26(60) N-{3-[4-(2-thien-2-ylethoxy)phenyl]propyl}-β-alaninetrifluoroacetate

HPLC retention time (minute): 3.34; MS (m/z): 334 (M+H)⁺.

Example 26(61)N-(3-{4-[2-(benzylsulfanyl)ethoxy]phenyl}propyl)-β-alaninetrifluoroacetate

HPLC retention time (minute): 3.44; MS (m/z): 374 (M+H)⁺.

Example 26(62) N-(3-{4-[3-(benzyloxy)propoxy]phenyl}propyl)-β-alaninetrifluoroacetate

HPLC retention time (minute): 3.38; MS (m/z): 372 (M+H)⁺.

Example 26(63) N-{3-[4-(3-phenoxypropoxy)phenyl]propyl}-β-alaninetrifluoroacetate

HPLC retention time (minute): 3.42; MS (m/z): 358 (M+H)⁺.

Example 26(64) N-(3-{4-[(9-phenylnonyl)oxy]phenyl}propyl)-β-alaninetrifluoroacetate

HPLC retention time (minute): 4.00; MS (m/z): 426 (M+H)⁺.

Example 26(65) N-(3-{4-[(8-phenyloctyl)oxy]phenyl}propyl)-β-alaninetrifluoroacetate

HPLC retention time (minute): 3.93; MS (m/z): 412 (M+H)⁺.

Example 26(66) N-{3-[4-(cyclohexylmethoxy)phenyl]propyl}-β-alaninetrifluoroacetate

HPLC retention time (minute): 3.55; MS (m/z): 320 (M+H)⁺, 219.

Example 26(67) N-{3-[4-(2-cyclopentylethoxy)phenyl]propyl}-β-alaninetrifluoroacetate

HPLC retention time (minute): 3.53; MS (m/z): 320 (M+H)⁺.

Example 26(68)N-[3-(4-{[5-(benzyloxy)pentyl]oxy}phenyl)propyl]-β-alaninetrifluoroacetate

HPLC retention time (minute): 3.53; MS (m/z): 400 (M+H)⁺.

Example 26(69) N-(3-({4-[4-(benzyloxy)butoxy]phenyl}propyl)-β-alaninetrifluoroacetate

HPLC retention time (minute): 3.45; MS (m/z): 386 (M+H)⁺.

Example 26(70) N-(3-{4-[(3-phenoxybenzyl)oxy]phenyl}propyl)-β-alaninetrifluoroacetate

HPLC retention time (minute): 3.58; MS (m/z): 406 (M+H)⁺, 219.

Example 26(71) N-{3-[4-(2-cyclohexylethoxy)phenyl]propyl}-β-alaninetrifluoroacetate

HPLC retention time (minute): 3.60; MS (m/z): 334 (M+H)⁺, 219.

Example 26(72) N-{3-[4-(cyclopentylmethoxy)phenyl]propyl}-β-alaninetrifluoroacetate

HPLC retention time (minute): 3.44; MS (m/z): 306 (M+H)⁺.

Example 26(73) N-[3-(4-isobutoxyphenyl)propyl]-β-alaninetrifluoroacetate

HPLC retention time (minute): 3.31; MS (m/z): 280 (M+H)⁺.

Example 26(74) N-(3-({4-[(4-methylpentyl)oxy]phenyl}propyl)-β-alaninetrifluoroacetate

HPLC retention time (minute): 3.51; MS (m/z): 308 (M+H)⁺.

Example 26(75) N-{3-[4-(3,3-dimethylbutoxy)phenyl]propyl}-β-alaninetrifluoroacetate

HPLC retention time (minute): 3.49; MS (m/z): 308 (M+H)⁺.

Example 26(76) N-(3-{4-[(2-propylpentyl)oxy]phenyl}propyl)-β-alaninetrifluoroacetate

HPLC retention time (minute): 3.71; MS (m/z): 336 (M+H)⁺.

Example 26(77) N-{3-[4-(3-cyclohexylpropoxy)phenyl]propyl}-β-alaninetrifluoroacetate

HPLC retention time (minute): 3.75; MS (m/z): 348 (M+H)⁺.

Example 26(78) N-(3-{4-[(4-chlorobenzyl)oxy]phenyl}propyl)-β-alaninetrifluoroacetate

HPLC retention time (minute): 3.42; MS (m/z): 350, 348 (M+H)⁺.

Example 26(79)N-(3-{4-[2-(4-tert-butylphenyl)ethoxy]phenyl}propyl)-β-alaninetrifluoroacetate

HPLC retention time (minute): 3.69; MS (m/z): 384 (M+H)⁺.

Example 26(80) N-(3-{4-[2-(2-naphthyl)ethoxy]phenyl}propyl)-β-alaninetrifluoroacetate

HPLC retention time (minute): 3.56; MS (m/z): 378 (M+H)⁺.

Example 26(81) N-{3-[4-(decyloxy)phenyl]propyl}-β-alaninetrifluoroacetate

HPLC retention time (minute): 3.99; MS (m/z): 364 (M+H)⁺.

Example 26(82) N-{2-[4-(2-thien-2-ylethoxy)phenyl]ethyl}-β-alaninetrifluoroacetate

HPLC retention time (minute): 3.27; MS (m/z): 320 (M+H)⁺.

Example 26(83) N-(2-{4-[(6-phenylhexyl)oxy]phenyl}ethyl)-β-alaninetrifluoroacetate

HPLC retention time (minute): 3.67; MS (m/z): 370 (M+H)⁺, 219.

Example 26(84) N-(2-{4-[3-(benzyloxy)propoxy]phenyl}ethyl)-β-alaninetrifluoroacetate

HPLC retention time (minute): 3.34; MS (m/z): 358 (M+H)⁺.

Example 26(85) N-(2-{4-[(7-phenylheptyl)oxy]phenyl}ethyl)-β-alaninetrifluoroacetate

HPLC retention time (minute): 3.77; MS (m/z): 384 (M+H)⁺.

Example 26(86) N-(2-{4-[(9-phenylnonyl)oxy]phenyl}ethyl)-β-alaninetrifluoroacetate

HPLC retention time (minute): 3.95; MS (m/z): 412 (M+H)⁺.

Example 26(87) N-(2-{4-[(8-phenyloctyl)oxy]phenyl}ethyl)-β-alaninetrifluoroacetate

HPLC retention time (minute): 3.86; MS (m/z): 398 (M+H)⁺.

Example 26(88) N-{2-[4-(2-cyclopentylethoxy)phenyl]ethyl}-β-alaninetrifluoroacetate

HPLC retention time (minute): 3.47; MS (m/z): 306 (M+H)⁺.

Example 26(89) N-[2-(4-{[5-(benzyloxy)pentyl]oxy}phenyl)ethyl]-β-alaninetrifluoroacetate

HPLC retention time (minute): 3.49; MS (m/z): 386 (M+H)⁺.

Example 26(90) N-(2-{4-[4-(benzyloxy)butoxy]phenyl}ethyl)-β-alaninetrifluoroacetate

HPLC retention time (minute): 3.40; MS (m/z): 372 (M+H)⁺.

Example 26(91) N-[2-(4-butoxyphenyl)ethyl]-β-alanine trifluoroacetate

HPLC retention time (minute): 3.23; MS (m/z): 266 (M+H)⁺.

Example 26(92) N-{2-[4-(cyclopentylmethoxy)phenyl]ethyl}-β-alaninetrifluoroacetate

HPLC retention time (minute): 3.38; MS (m/z): 292 (M+H).

Example 26(93) N-[2-(4-isobutoxyphenyl)ethyl]-β-alanine trifluoroacetate

HPLC retention time (minute): 3.23; MS (m/z): 266 (M+H)⁺.

Example 26(94) N-(2-{4-[(4-methylpentyl)oxy]phenyl}ethyl)-β-alaninetrifluoroacetate

HPLC retention time (minute): 3.44; MS (m/z): 294 (M+H)⁺.

Example 26(95) N-(2-{4-[(2-propylpentyl)oxy]phenyl}ethyl)-β-alaninetrifluoroacetate

HPLC retention time (minute): 3.64; MS (m/z): 322 (M+H)⁺, 219.

Example 26(96) N-{2-[4-(pentyloxy)phenyl]ethyl}-β-alaninetrifluoroacetate

HPLC retention time (minute): 3.34; MS (m/z): 280 (M+H)⁺.

Example 26(97) N-{2-[4-(hexyloxy)phenyl]ethyl}-β-alaninetrifluoroacetate

HPLC retention time (minute): 3.45; MS (m/z): 294 (M+H)⁺.

Example 26(98) N-{2-[4-(heptyloxy)phenyl]ethyl}-β-alaninetrifluoroacetate

HPLC retention time (minute): 3.56; MS (m/z): 308 (M+H)⁺, 219.

Example 26(99) N-{2-[4-(octyloxy)phenyl]ethyl}-β-alaninetrifluoroacetate

HPLC retention time (minute): 3.67; MS (m/z): 322 (M+H)⁺.

Example 26(100) N-(2-{4-[(4-chlorobenzyl)oxy]phenyl}ethyl)-β-alaninetrifluoroacetate

HPLC retention time (minute): 3.38; MS (m/z): 336, 334 (M+H)⁺.

Example 26(101)N-(2-{4-[2-(4-tert-butylphenyl)ethoxy]phenyl}ethyl)-β-alaninetrifluoroacetate

HPLC retention time (minute): 3.66; MS (m/z): 370 (M+H)⁺.

Example 26(102) N-(2-{4-[2-(2-naphthyl)ethoxy]phenyl}ethyl)-β-alaninetrifluoroacetate

HPLC retention time (minute): 3.49; MS (m/z): 364 (M+H)⁺.

Example 26(103)N-(2-{4-[2-(4-methylphenyl)ethoxy]phenyl}ethyl)-β-alaninetrifluoroacetate

HPLC retention time (minute): 3.40; MS (m/z): 328 (M+H)⁺.

Example 26(104) N-{2-[4-(nonyloxy)phenyl]ethyl}-β-alaninetrifluoroacetate

HPLC retention time (minute): 3.80; MS (m/z): 336 (M+H)⁺.

Example 26(105)N-(2-{4-[2-(3-methylphenyl)ethoxy]phenyl}ethyl)-β-alaninetrifluoroacetate

HPLC retention time (minute): 3.40; MS (m/z): 328 (M+H)⁺.

Example 26(106) N-{2-[4-(decyloxy)phenyl]ethyl}-β-alaninetrifluoroacetate

HPLC retention time (minute): 3.89; MS (m/z): 350 (M+H)⁺.

Example 26(107)N-(2-{4-[2-(2-methylphenyl)ethoxy]phenyl}ethyl)-β-alaninetrifluoroacetate

HPLC retention time (minute): 3.40; MS (m/z): 328 (M+H)⁺.

Example 26(108)N-[2-(3-{2-[4-(benzyloxy)phenyl]ethoxy}phenyl)ethyl]-β-alaninetrifluoroacetate

HPLC retention time (minute): 3.58; MS (m/z): 420 (M+H)⁺.

Example 26(109) N-{2-[3-(2-phenoxyethoxy)phenyl]ethyl}-β-alaninetrifluoroacetate

HPLC retention time (minute): 3.27; MS (m/z): 330 (M+H)⁺.

Example 26(110) N-{2-[3-(3-phenylpropoxy)phenyl]ethyl}-β-alaninetrifluoroacetate

HPLC retention time (minute): 3.38; MS (m/z): 328 (M+H)⁺.

Example 26(111) N-{2-[3-(4-phenylbutoxy)phenyl]ethyl}-β-alaninetrifluoroacetate

HPLC retention time (minute): 3.47; MS (m/z): 342 (M+H)⁺.

Example 26(112) N-(2-{3-[(5-phenylpentyl)oxy]phenyl}ethyl)-β-alaninetrifluoroacetate

HPLC retention time (minute): 3.56; MS (m/z): 356 (M+H)⁺, 219.

Example 26(113)N-(2-{3-[2-(benzylsulfanyl)ethoxy]phenyl}ethyl)-β-alaninetrifluoroacetate

HPLC retention time (minute): 3.38; MS (m/z): 360 (M+H)⁺.

Example 26(114) N-(2-{3-[(6-phenylhexyl)oxy]phenyl}ethyl)-β-alaninetrifluoroacetate

HPLC retention time (minute): 3.64; MS (m/z): 370 (M+H)⁺.

Example 26(115) N-(2-{3-[3-(benzyloxy)propoxy]phenyl)}ethyl)-β-alaninetrifluoroacetate

HPLC retention time (minute): 3.34; MS (m/z): 358 (M+H)⁺.

Example 26(116) N-(2-{3-[(7-phenylheptyl)oxy]phenyl}ethyl)-β-alaninetrifluoroacetate

HPLC retention time (minute): 3.75; MS (m/z): 384 (M+H)⁺.

Example 26(117) N-(2-{3-[(9-phenylnonyl)oxy]phenyl}ethyl)-β-alaninetrifluoroacetate

HPLC retention time (minute): 3.95; MS (m/z): 412 (M+H)⁺.

Example 26(118) N-(2-{3-[(8-phenyloctyl)oxy]phenyl}ethyl)-β-alaninetrifluoroacetate

HPLC retention time (minute): 3.84; MS (m/z): 398 (M+H)⁺.

Example 26(119) N-{2-[3-(cyclohexylmethoxy)phenyl]ethyl}-β-alaninetrifluoroacetate

HPLC retention time (minute): 3.45; MS (m/z): 320, 306 (M+H)⁺.

Example 26(120) N-{2-[3-(2-cyclopentylethoxy)phenyl]ethyl}-β-alaninetrifluoroacetate

HPLC retention time (minute): 3.45; MS (m/z): 306 (M+H)⁺.

Example 26(121)N-[2-(3-{[5-(benzyloxy)pentyl]oxy}phenyl)ethyl]-β-alaninetrifluoroacetate

HPLC retention time (minute): 3.47; MS (m/z): 386 (M+H)⁺.

Example 26(122) N-(2-{3-[4-(benzyloxy)butoxy]phenyl}ethyl)-β-alaninetrifluoroacetate

HPLC retention time (minute): 3.42; MS (m/z): 372 (M+H)⁺.

Example 26(123) N-(2-{3-[(3-phenoxybenzyl)oxy]phenyl}ethyl)-β-alaninetrifluoroacetate

HPLC retention time (minute): 3.51; MS (m/z): 392 (M+H)⁺.

Example 26(124) N-{2-[3-(2-cyclohexylethoxy)phenyl]ethyl}-β-alaninetrifluoroacetate

HPLC retention time (minute): 3.58; MS (m/z): 320 (M+H)⁺, 219.

Example 26(125) N-[2-(3-butoxyphenyl)ethyl]-β-alanine trifluoroacetate

HPLC retention time (minute): 3.22; MS (m/z): 266 (M+H)⁺.

Example 26(126) N-{2-[3-(cyclopentylmethoxy)phenyl]ethyl}-β-alaninetrifluoroacetate

HPLC retention time (minute): 3.40; MS (m/z): 336, 320, 292 (M+H)⁺.

Example 26(127) N-{2-[3-(benzyloxy)phenyl]ethyl}-β-alaninetrifluoroacetate

HPLC retention time (minute): 3.23; MS (m/z): 300 (M+H)⁺.

Example 26(128) N-{2-[3-(2-phenylethoxy)phenyl]ethyl}-β-alaninetrifluoroacetate

HPLC retention time (minute): 3.33; MS (m/z): 314 (M+H)⁺.

Example 26(129) N-[2-(3-isobutoxyphenyl)ethyl]-β-alaninetrifluoroacetate

HPLC retention time (minute): 3.23; MS (m/z): 266 (M+H)⁺.

Example 26(130) N-(2-{3-[(4-methylpentyl)oxy]phenyl}ethyl)-β-alaninetrifluoroacetate

HPLC retention time (minute): 3.44; MS (m/z): 294 (M+H)⁺.

Example 26(131) N-{2-[3-(3,3-dimethylbutoxy)phenyl]ethyl}-β-alaninetrifluoroacetate

HPLC retention time (minute): 3.40; MS (m/z): 294 (M+H)⁺.

Example 26(132) N-(2-{3-[(2-propylpentyl)oxy]phenyl}ethyl)-β-alaninetrifluoroacetate

HPLC retention time (minute): 3.62; MS (m/z): 322 (M+H)⁺.

Example 26(133) N-{2-[3-(3-cyclohexylpropoxy)phenyl]ethyl}-β-alaninetrifluoroacetate

HPLC retention time (minute): 3.66; MS (m/z): 334 (M+H)⁺.

Example 26(134) N-{2-[3-(pentyloxy)phenyl]ethyl}-β-alaninetrifluoroacetate

HPLC retention time (minute): 3.33; MS (m/z): 280 (M+H)⁺.

Example 26(135) N-{2-[3-(hexyloxy)phenyl]ethyl}-β-alaninetrifluoroacetate

HPLC retention time (minute): 3.44; MS (m/z): 294 (M+H)⁺.

Example 26(136) N-{2-[3-(heptyloxy)phenyl]ethyl}-β-alaninetrifluoroacetate

HPLC retention time (minute): 3.56; MS (m/z): 308 (M+H)⁺.

Example 26(137) N-{2-[3-(octyloxy)phenyl]ethyl}-β-alaninetrifluoroacetate

HPLC retention time (minute): 3.67; MS (m/z): 322 (M+H)⁺.

Example 26(138) N-(2-{3-[(4-chlorobenzyl)oxy]phenyl}ethyl)-β-alaninetrifluoroacetate

HPLC retention time (minute): 3.37; MS (m/z): 336, 334 (M+H)⁺.

Example 26(139)N-(2-{3-[2-(4-tert-butylphenyl)ethoxy]phenyl}ethyl)-β-alaninetrifluoroacetate

HPLC retention time (minute): 3.62; MS (m/z): 370 (M+H)⁺.

Example 26(140) N-(2-{3-[2-(2-naphthyl)ethoxy]phenyl}ethyl)-β-alaninetrifluoroacetate

HPLC retention time (minute): 3.47; MS (m/z): 364 (M+H)⁺.

Example 26(141)N-(2-{3-[2-(4-methylphenyl)ethoxy]phenyl}ethyl)-β-alaninetrifluoroacetate

HPLC retention time (minute): 3.40; MS (m/z): 328 (M+H)⁺.

Example 26(142) N-{2-[3-(nonyloxy)phenyl]ethyl}-β-alaninetrifluoroacetate

HPLC retention time (minute): 3.78; MS (m/z): 336 (M+H)⁺.

Example 26(143)N-(2-{3-[2-(3-methylphenyl)ethoxy]phenyl}ethyl)-β-alaninetrifluoroacetate

HPLC retention time (minute): 3.40; MS (m/z): 328 (M+H)⁺.

Example 26(144) N-{2-[3-(decyloxy)phenyl]ethyl}-β-alaninetrifluoroacetate

HPLC retention time (minute): 3.88; MS (m/z): 350 (M+H)⁺.

Example 26(145)N-(2-{3-[2-(2-methylphenyl)ethoxy]phenyl}ethyl)-β-alaninetrifluoroacetate

HPLC retention time (minute): 3.38; MS (m/z): 328 (M+H)⁺.

Example 26(146) N-(3-{2-[4-(benzyloxy)phenyl]ethoxy}benzyl)-β-alaninetrifluoroacetate

HPLC retention time (minute): 3.55; MS (m/z): 406 (M+H)⁺.

Example 26(147) N-[3-(3-phenylpropoxy)benzyl]-β-alanine trifluoroacetate

HPLC retention time (minute): 3.33; MS (m/z): 314 (M+H)⁺.

Example 26(148) N-[3-(4-phenylbutoxy)benzyl]-β-alanine trifluoroacetate

HPLC retention time (minute): 3.42; MS (m/z): 328 (M+H)⁺.

Example 26(149) N-{3-[(5-phenylpentyl)oxy]benzyl}-β-alaninetrifluoroacetate

HPLC retention time (minute): 3.51; MS (m/z): 342 (M+H)⁺.

Example 26(150) N-{3-[2-(benzylsulfanyl)ethoxy]benzyl}-β-alaninetrifluoroacetate

HPLC retention time (minute): 3.34; MS (m/z): 360, 346 (M+H)⁺.

Example 26(151) N-{3-[(6-phenylhexyl)oxy]benzyl}-β-alaninetrifluoroacetate

HPLC retention time (minute): 3.60; MS (m/z): 356 (M+H)⁺.

Example 26(152) N-{3-[3-(benzyloxy)propoxy]benzyl}-β-alaninetrifluoroacetate

HPLC retention time (minute): 3.29; MS (m/z): 344 (M+H)⁺.

Example 26(153) N-{3-[(7-phenylheptyl)oxy]benzyl}-β-alaninetrifluoroacetate

HPLC retention time (minute): 3.69; MS (m/z): 370 (M+H)⁺.

Example 26(154) N-[3-(3-phenoxypropoxy)benzyl]-β-alaninetrifluoroacetate

HPLC retention time (minute): 3.31; MS (m/z): 330 (M+H)⁺.

Example 26(155) N-{3-[(9-phenylnonyl)oxy]benzyl}-β-alaninetrifluoroacetate

HPLC retention time (minute): 3.88; MS (m/z): 330 (M+H)⁺.

Example 26(156) N-{3-[(8-phenyloctyl)oxy]benzyl}-β-alaninetrifluoroacetate

HPLC retention time (minute): 3.77; MS (m/z): 384 (M+H)⁺.

Example 26(157) N-[3-(2-cyclopentylethoxy)benzyl]-β-alaninetrifluoroacetate

HPLC retention time (minute): 3.38; MS (m/z): 292 (M+H)⁺.

Example 26(158) N-(3-({[5-(benzyloxy)pentyl]oxy}benzyl)-β-alaninetrifluoroacetate

HPLC retention time (minute): 3.42; MS (m/z): 372 (M+H)⁺.

Example 26(159) N-{3-[4-(benzyloxy)butoxy]benzyl}-β-alaninetrifluoroacetate

HPLC retention time (minute): 3.33; MS (m/z): 358 (M+H)⁺.

Example 26(160) N-{3-[(3-phenoxybenzyl)oxy]benzyl}-β-alaninetrifluoroacetate

HPLC retention time (minute): 3.45; MS (m/z): 378 (M+H)⁺.

Example 26(161) N-[3-(2-cyclohexylethoxy)benzyl]-β-alaninetrifluoroacetate

HPLC retention time (minute): 3.45; MS (m/z): 306 (M+H)⁺.

Example 26(162) N-(3-butoxybenzyl)-β-alanine trifluoroacetate

HPLC retention time (minute): 3.14; MS (m/z): 252 (M+H)⁺.

Example 26(163) N-[3-(cyclopentylmethoxy)benzyl]-β-alaninetrifluoroacetate

HPLC retention time (minute): 3.29; MS (m/z): 278 (M+H)⁺.

Example 26(164) N-[3-(benzyloxy)benzyl]-β-alanine trifluoroacetate

HPLC retention time (minute): 3.16; MS (m/z): 286 (M+H)⁺.

Example 26(165) N-[3-(2-phenylethoxy)benzyl]-β-alanine trifluoroacetate

HPLC retention time (minute): 3.25; MS (m/z): 300 (M+H)⁺.

Example 26(166) N-(3-isobutoxybenzyl)-β-alanine trifluoroacetate

HPLC retention time (minute): 3.16; MS (m/z): 252 (M+H)⁺.

Example 26(167) N-{3-[(4-methylpentyl)oxy]benzyl}-β-alaninetrifluoroacetate

HPLC retention time (minute): 3.36; MS (m/z): 280 (M+H)⁺.

Example 26(168) N-[3-(3,3-dimethylbutoxy)benzyl]-β-alaninetrifluoroacetate

HPLC retention time (minute): 3.33; MS (m/z): 280 (M+H)⁺.

Example 26(169) N-{3-[(2-propylpentyl)oxy]benzyl}-β-alaninetrifluoroacetate

HPLC retention time (minute): 3.56; MS (m/z): 308 (M+H)⁺.

Example 26(170) N-[3-(3-cyclohexylpropoxy)benzyl]-β-alaninetrifluoroacetate

HPLC retention time (minute): 3.58; MS (m/z): 320 (M+H)⁺.

Example 26(171) N-[3-(pentyloxy)benzyl]-β-alanine trifluoroacetate

HPLC retention time (minute): 3.25; MS (m/z): 266 (M+H)⁺.

Example 26(172) N-[3-(hexyloxy)benzyl]-β-alanine trifluoroacetate

HPLC retention time (minute): 3.40; MS (m/z): 280 (M+H)⁺.

Example 26(173) N-[3-(heptyloxy)benzyl]-β-alanine trifluoroacetate

HPLC retention time (minute): 3.47; MS (m/z): 294 (M+H)⁺.

Example 26(174) N-[3-(octyloxy)benzyl]-β-alanine trifluoroacetate

HPLC retention time (minute): 3.60; MS (m/z): 308 (M+H)⁺.

Example 26(175) N-({3-[(4-chlorobenzyl)oxy]benzyl}-β-alaninetrifluoroacetate

HPLC retention time (minute): 3.31; MS (m/z): 322, 320 (M+H)⁺.

Example 26(176) N-{3-[2-(4-tert-butylphenyl)ethoxy]benzyl}-β-alaninetrifluoroacetate

HPLC retention time (minute): 3.58; MS (m/z): 356 (M+H)⁺.

Example 26(177) N-{3-[2-(2-naphthyl)ethoxy]benzyl}-β-alaninetrifluoroacetate

HPLC retention time (minute): 3.42; MS (m/z): 350 (M+H)⁺.

Example 26(178) N-{(3-[2-(4-methylphenyl)ethoxy]benzyl}-β-alaninetrifluoroacetate

HPLC retention time (minute): 3.34; MS (m/z): 314 (M+H)⁺.

Example 26(179) N-[3-(nonyloxy)benzyl]-β-alanine trifluoroacetate

HPLC retention time (minute): 3.71; MS (m/z): 322 (M+H)⁺.

Example 26(180) N-{3-[2-(3-methylphenyl)ethoxy]benzyl}-β-alaninetrifluoroacetate

HPLC retention time (minute): 3.34; MS (m/z): 314 (M+H)⁺.

Example 26(181) N-[3-(decyloxy)benzyl]-β-alanine trifluoroacetate

HPLC retention time (minute): 3.80; MS (m/z): 336 (M+H)⁺.

Example 26(182) N-{3-[2-(2-methylphenyl)ethoxy]benzyl}-β-alaninetrifluoroacetate

HPLC retention time (minute): 3.33; MS (m/z): 314 (M+H)⁺.

Example 26(183)N-[3-(3-{2-[4-(benzyloxy)phenyl]ethoxy}phenyl)propyl]-β-alaninetrifluoroacetate

HPLC retention time (minute): 3.64; MS (m/z): 434 (M+H)⁺.

Example 26(184) N-{3-[3-(2-phenoxyethoxy)phenyl]propyl}-β-alaninetrifluoroacetate

HPLC retention time (minute): 3.33; MS (m/z): 344 (M+H)⁺.

Example 26(185) N-{(3-[3-(3-phenylpropoxy)phenyl]propyl}-β-alaninetrifluoroacetate

HPLC retention time (minute): 3.45; MS (m/z): 342 (M+H)⁺.

Example 26(186) N-{3-[3-(4-phenylbutoxy)phenyl]propyl}-β-alaninetrifluoroacetate

HPLC retention time (minute): 3.53; MS (m/z): 356 (M+H)⁺.

Example 26(187) N-(3-{3-[(5-phenylpentyl)oxy]phenyl}propyl)-β-alaninetrifluoroacetate

HPLC retention time (minute): 3.64; MS (m/z): 370 (M+H)⁺.

Example 26(188) N-(3-({3-[(6-phenylhexyl)oxy]phenyl}propyl)-β-alaninetrifluoroacetate

HPLC retention time (minute): 3.73; MS (m/z): 384 (M+H)⁺.

Example 26(189) N-(3-{3-[3-(benzyloxy)propoxy]phenyl}propyl)-β-alaninetrifluoroacetate

HPLC retention time (minute): 3.40; MS (m/z): 372 (M+H)⁺.

Example 26(190) N-(3-{3-[(7-phenylheptyl)oxy]phenyl}propyl)-β-alaninetrifluoroacetate

HPLC retention time (minute): 3.82; MS (m/z): 398 (M+H)⁺.

Example 26(191) N-(3-({3-[(9-phenylnonyl)oxy]phenyl}propyl)-β-alaninetrifluoroacetate

HPLC retention time (minute): 4.00; MS (m/z): 426 (M+H)⁺.

Example 26(192) N-(3-({3-[(8-phenyloctyl)oxy]phenyl}propyl)-β-alaninetrifluoroacetate

HPLC retention time (minute): 3.89; MS (m/z): 412 (M+H)⁺.

Example 26(193) N-{3-[3-(2-cyclopentylethoxy)phenyl]propyl}-β-alaninetrifluoroacetate

HPLC retention time (minute): 3.51; MS (m/z): 320 (M+H)⁺.

Example 26(194)N-[3-(3-{[5-(benzyloxy)pentyl]oxy}phenyl)propyl]-β-alaninetrifluoroacetate

HPLC retention time (minute): 3.51; MS (m/z): 400 (M+H)⁺.

Example 26(195) N-(3-{3-[4-(benzyloxy)butoxy]phenyl}propyl)-β-alaninetrifluoroacetate

HPLC retention time (minute): 3.45; MS (m/z): 386 (M+H)⁺.

Example 26(196) N-(3-{3-[(3-phenoxybenzyl)oxy]phenyl}propyl)-β-alaninetrifluoroacetate

HPLC retention time (minute): 3.55; MS (m/z): 406 (M+H)⁺.

Example 26(197) N-{3-[3-(2-cyclohexylethoxy)phenyl]propyl}-β-alaninetrifluoroacetate

HPLC retention time (minute): 3.60; MS (m/z): 334 (M+H)⁺.

Example 26(198) N-[3-(3-butoxyphenyl)propyl]-β-alanine trifluoroacetate

HPLC retention time (minute): 3.29; MS (m/z): 280 (M+H)⁺.

Example 26(199) N-{3-[3-(cyclopentylmethoxy)phenyl]propyl}-β-alaninetrifluoroacetate

HPLC retention time (minute): 3.42; MS (m/z): 306 (M+H)⁺.

Example 26(200) N-{3-[3-(benzyloxy)phenyl]propyl}-β-alaninetrifluoroacetate

HPLC retention time (minute): 3.29; MS (m/z): 314 (M+H)⁺.

Example 26(201) N-{3-[3-(2-phenylethoxy)phenyl]propyl}-β-alaninetrifluoroacetate

HPLC retention time (minute): 3.38; MS (m/z): 328 (M+H)⁺.

Example 26(202) N-[3-(3-isobutoxyphenyl)propyl]-β-alaninetrifluoroacetate

HPLC retention time (minute): 3.29; MS (m/z): 280 (M+H)⁺.

Example 26(203) N-(3-{3-[(4-methylpentyl)oxy]phenyl}propyl)-β-alaninetrifluoroacetate

HPLC retention time (minute): 3.49; MS (m/z): 308 (M+H)⁺.

Example 26(204) N-{3-[3-(3,3-dimethylbutoxy)phenyl]propyl}-β-alaninetrifluoroacetate

HPLC retention time (minute): 3.45; MS (m/z): 308 (M+H)⁺.

Example 26(205) N-(3-{3-[(2-propylpentyl)oxy]phenyl}propyl)-β-alaninetrifluoroacetate

HPLC retention time (minute): 3.69; MS (m/z): 336 (M+H)⁺.

Example 26(206) N-{3-[3-(3-cyclohexylpropoxy)phenyl]propyl}-β-alaninetrifluoroacetate

HPLC retention time (minute): 3.71; MS (m/z): 348 (M+H)⁺.

Example 26(207) N-{3-[3-(pentyloxy)phenyl]propyl}-β-alaninetrifluoroacetate

HPLC retention time (minute): 3.42; MS (m/z): 294 (M+H)⁺.

Example 26(208) N-{3-[3-(hexyloxy)phenyl]propyl}-β-alaninetrifluoroacetate

HPLC retention time (minute): 3.51; MS (m/z): 308 (M+H)⁺.

Example 26(209) N-{3-[3-(heptyloxy)phenyl]propyl}-β-alaninetrifluoroacetate

HPLC retention time (minute): 3.60; MS (m/z): 322 (M+H)⁺.

Example 26(210) N-{3-[3-(octyloxy)phenyl]propyl}-β-alaninetrifluoroacetate

HPLC retention time (minute): 3.71; MS (m/z): 336 (M+H)⁺.

Example 26(211) N-(3-{3-[(4-chlorobenzyl)oxy]phenyl}propyl)-β-alaninetrifluoroacetate

HPLC retention time (minute): 3.42; MS (m/z): 350, 348 (M+H)⁺.

Example 26(212)N-(3-{3-[2-(4-tert-butylphenyl)ethoxy]phenyl}propyl)-β-alaninetrifluoroacetate

HPLC retention time (minute): 3.67; MS (m/z): 384 (M+H)⁺.

Example 26(213) N-(3-{3-[2-(2-naphthyl)ethoxy]phenyl}propyl)-β-alaninetrifluoroacetate

HPLC retention time (minute): 3.53; MS (m/z): 378 (M+H)⁺.

Example 26(214)N-(3-{3-[2-(4-methylphenyl)ethoxy]phenyl}propyl)-β-alaninetrifluoroacetate

HPLC retention time (minute): 3.45; MS (m/z): 342 (M+H)⁺.

Example 26(215) N-{3-[3-(nonyloxy)phenyl]propyl}-β-alaninetrifluoroacetate

HPLC retention time (minute): 3.84; MS (m/z): 350 (M+H)⁺.

Example 26(216)N-(3-{3-[2-(3-methylphenyl)ethoxy]phenyl}propyl)-β-alaninetrifluoroacetate

HPLC retention time (minute): 3.45; MS (m/z): 342 (M+H)⁺.

Example 26(217) N-{3-[3-(decyloxy)phenyl]propyl}-β-alaninetrifluoroacetate

HPLC retention time (minute): 3.93; MS (m/z): 364 (M+H)⁺.

Example 26(218)N-(3-{3-[2-(2-methylphenyl)ethoxy]phenyl}propyl)-β-alaninetrifluoroacetate

HPLC retention time (minute): 3.44; MS (m/z): 342 (M+H)⁺.

Example 26(219)N-(3-{4-[3-(4-fluorophenyl)propoxy]phenyl}propyl)-β-alaninetrifluoroacetate

HPLC retention time (minute): 3.49; MS (m/z): 360 (M+H)⁺.

Example 26(220)N-(3-{4-[3-(4-bromophenyl)propoxy]phenyl}propyl)-β-alaninetrifluoroacetate

HPLC retention time (minute): 3.60; MS (m/z): 422, 420 (M+H)⁺.

Example 26(221)N-[3-(4-{3-[4-(trifluoromethyl)phenyl]propoxy}phenyl)propyl]-β-alaninetrifluoroacetate

HPLC retention time (minute): 3.62; MS (m/z): 410 (M+H)⁺.

Example 26(222)N-(3-{4-[3-(3-methylphenyl)propoxy]phenyl}propyl)-β-alaninetrifluoroacetate

HPLC retention time (minute): 3.55; MS (m/z): 356 (M+H)⁺.

Example 26(223)N-(3-{4-[3-(2-chlorophenyl)propoxy]phenyl}propyl)-β-alaninetrifluoroacetate

HPLC retention time (minute): 3.55; MS (m/z): 378, 376 (M+H)⁺.

Example 26(224)N-(3-{4-[3-(2,6-dichlorophenyl)propoxy]phenyl}propyl)-β-alaninetrifluoroacetate

HPLC retention time (minute): 3.64; MS (m/z): 412, 410 (M+H)⁺.

Example 26(225)N-(3-{4-[3-(4-chlorophenyl)propoxy]phenyl}propyl)-β-alaninetrifluoroacetate

HPLC retention time (minute): 3.58; MS (m/z): 378, 376 (M+H)⁺.

Example 26(226)N-(3-{4-[3-(2-methylphenyl)propoxy]phenyl}propyl)-β-alaninetrifluoroacetate

HPLC retention time (minute): 3.49; MS (m/z): 356 (M+H)⁺.

Example 26(227)N-(3-{4-[3-(3-chlorophenyl)propoxy]phenyl}propyl)-β-alaninetrifluoroacetate

HPLC retention time (minute): 3.56; MS (m/z): 378, 376 (M+H)⁺.

Example 26(228)N-(3-({4-[3-(4-methoxyphenyl)propoxy]phenyl}propyl)-β-alaninetrifluoroacetate

HPLC retention time (minute): 3.44; MS (m/z): 372 (M+H)⁺.

Example 26(229)N-(3-{4-[3-(2-bromophenyl)propoxy]phenyl}propyl)-β-alaninetrifluoroacetate

HPLC retention time (minute): 3.58; MS (m/z): 422, 420 (M+H)⁺.

Example 26(230)N-(3-({4-[3-(3-nitrophenyl)propoxy]phenyl}propyl)-β-alaninetrifluoroacetate

HPLC retention time (minute): 3.44; MS (m/z): 387 (M+H)⁺.

Example 26(231)N-(3-({4-[3-(3-fluorophenyl)propoxy]phenyl}propyl)-β-alaninetrifluoroacetate

HPLC retention time (minute): 3.49; MS (m/z): 360 (M+H)⁺.

Example 26(232)N-(3-{4-[3-(3,4-dimethoxyphenyl)propoxy]phenyl}propyl)-β-alaninetrifluoroacetate

HPLC retention time (minute): 3.34; MS (m/z): 402 (M+H)⁺.

Example 26(233)N-(3-{4-[3-(3-phenoxyphenyl)propoxy]phenyl}propyl)-β-alaninetrifluoroacetate

HPLC retention time (minute): 3.71; MS (m/z): 434 (M+H)⁺.

Example 26(234)N-(3-{4-[3-(3,4-difluorophenyl)propoxy]phenyl}propyl)-β-alaninetrifluoroacetate

HPLC retention time (minute): 3.53; MS (m/z): 378 (M+H)⁺.

Example 26(235)N-(3-({4-[3-(3,4,5-trimethoxyphenyl)propoxy]phenyl}propyl)-β-alaninetrifluoroacetate

HPLC retention time (minute): 3.31; MS (m/z): 432 (M+H)⁺.

Example 26(236)N-[3-(4-{3-[3-(trifluoromethoxy)phenyl]propoxy}phenyl)propyl]-β-alaninetrifluoroacetate

HPLC retention time (minute): 3.64; MS (m/z): 426 (M+H)⁺.

Example 26(237)N-[3-(4-{3-[2,5-bis(trifluoromethyl)phenyl]propoxy}phenyl)propyl]-β-alaninetrifluoroacetate

HPLC retention time (minute): 3.69; MS (m/z): 478 (M+H)⁺.

Example 26(238)N-(3-{4-[3-(3-bromophenyl)propoxy]phenyl}propyl)-β-alaninetrifluoroacetate

HPLC retention time (minute): 3.60; MS (m/z): 422, 420 (M+H)⁺.

Example 26(239)N-[3-(4-{3-[3,5-bis(trifluoromethyl)phenyl]propoxy}phenyl)propyl]-β-alaninetrifluoroacetate

HPLC retention time (minute): 3.75; MS (m/z): 478 (M+H)⁺.

Example 26(240)N-[3-(4-{3-[3-(trifluoromethyl)phenyl]propoxy}phenyl)propyl]-β-alaninetrifluoroacetate

HPLC retention time (minute): 3.60; MS (m/z): 410 (M+H)⁺.

Example 26(241) N-{3-[4-(3-phenylbutoxy)phenyl]propyl}-β-alaninetrifluoroacetate

HPLC retention time (minute): 3.53; MS (m/z): 356 (M+H)⁺.

Example 26(242)N-{3-[4-(bicyclo[4.2.0]octa-1,3,5-trien-7-ylmethoxy)phenyl]propyl}-β-alaninetrifluoroacetate

HPLC retention time (minute): 3.44; MS (m/z): 340 (M+H)⁺.

Example 26(243)N-{3-[4-(2-methyl-3-phenylpropoxy)phenyl]propyl}-β-alaninetrifluoroacetate

HPLC retention time (minute): 3.55; MS (m/z): 356 (M+H)⁺.

Example 26(244) N-{3-[4-(3,3-diphenylpropoxy)phenyl]propyl}-β-alaninetrifluoroacetate

HPLC retention time (minute): 3.62; MS (m/z): 418 (M+H)⁺.

Example 27 N-{(3-[4-(4-phenylbutoxy)phenyl]propyl}-β-alaninehydrochloride

Step A:

To a suspension of chlorotrityl resin (manufactured by ArgonautTechnology; Cat No. 800380) (1.00 mmol/g, 1.0 g, 1.0 mmol) indichloromethane (5 mL), a solution of the compound (323 mg) prepared inExample 24 in a mixed solvent of N,N-diisopropylethylamine (0.70 mL) anddichloromethane (5 mL) was dropped at 0° C. After washing withdichloromethane (2 mL), the mixture was shaken at room temperature for 5hours. Then, the resin was taken up by filtration and washedsuccessively with a mixed solvent(dichloromethane:methanol:diisopropylethylamine=51:6:3) 3 times,dichloromethane 3 times, N,N-dimethylformamide 2 times anddichloromethane 2 times and dried to give a phenol resin (1.195 g).

Step B:

To the phenol resin (100 mg), 4-phenylbutan-1-ol (0.42 mmol) was addedat room temperature, followed by the addition of dry tetrahydrofuran(0.4 mL) and dichloromethane (0.4 mL). At room temperature,tri-n-butylphosphine (0.42 mmol) was added dropwise thereto and further1,1′-azobis(N,N-dimethylformamide) (0.42 mmol) was added. The mixturewas shaken at room temperature for 5 hours. The resin was taken up byfiltration, washed with a mixed solvent(dichloromethane:tetrahydrofuran=1:1) 4 times and dichloromethane 2times and then dried to give a phenyl ether resin (about 100 mg).

Step C:

To the phenyl ether resin (about 100 mg), acetic acid (0.2 mL),trifluoroethanol (0.2 mL) and dichloromethane (0.6 mL) were added atroom temperature and the mixture was shaken at room temperature for 3hours. The resin was taken up by filtration and washed with a mixedsolvent (acetic acid:trifluoroethanol:dichloromethane=1:1:3) 2 times anddichloromethane 4 times. The filtrate was concentrated and the residuewas purified by silica gel column chromatography (hexane:ethylacetate=5:1 to ethyl acetate) to thereby giveN-(tert-butoxycarbonyl)-N-{3-[4-(4-phenylbutoxy)phenyl]propyl}-β-alanine(2 mg; Boc compound).

Step D:

To the Boc compound, 4 N hydrogen chloride-ethyl acetate solution (1 mL)was added at room temperature, followed by stirring for 1 hour. Thereaction mixture was concentrated to give the title compound (2 mg)having the following physical properties.

TLC: Rf 0.20 (chloroform:methanol:aqueous ammonia=80:20:4);

¹H-NMR (CD₃OD): δ 1.76 (m, 4H), 1.96 (m, 2H), 2.68 (m, 6H), 3.01 (m,2H), 3.24 (t, 2H), 3.94 (m, 2H), 6.83 (d, 2H), 7.17 (m, 7H).

Examples 27(1) to 27(9)

The procedure of Example 27 was similarly carried out, except for usinga corresponding compound as a substitute for 4-phenylbutan-1-ol tothereby give the following compounds. In the case of the compound ofExample 27(9), the step D was omitted.

Example 27(1) N-(3-{4-[(6-phenylhexyl)oxy]phenyl}propyl)-β-alaninehydrochloride

TLC: Rf 0.29 (chloroform:methanol:aqueous ammonia=80:20:4);

¹H-NMR (CD₃OD): δ 1.42 (m, 4H), 1.64 (m, 2H), 1.74 (m, 2H), 1.96 (m,2H), 2.66 (m, 6H), 3.01 (m, 2H), 3.24 (t, 2H), 3.91 (t, 2H), 6.83 (d,2H), 7.13 (m, 5H), 7.22 (m, 2H).

Example 27(2) N-(3-{4-[(7-phenylheptyl)oxy]phenyl}propyl)-β-alaninehydrochloride

TLC: Rf 0.31 (chloroform:methanol:aqueous ammonia=80:20:4);

¹H-NMR (CD₃OD): δ 1.38 (m, 6H), 1.62 (m, 2H), 1.72 (m, 2H), 1.96 (m,2H), 2.66 (m, 6H), 3.01 (m, 2H), 3.23 (t, 2H), 3.92 (t, 2H), 6.83 (d,2H), 7.12 (m, 5H), 7.23 (m, 2H).

Example 27(3) N-[3-(4-butoxyphenyl)propyl]-β-alanine hydrochloride

TLC: Rf 0.21 (chloroform:methanol:aqueous ammonia=80:20:4);

¹H-NMR (CD₃OD): δ 0.97 (t, 3H), 1.47 (m, 2H), 1.73 (m, 2H), 1.96 (m,2H), 2.67 (m, 4H), 3.01 (m, 2H), 3.23 (t, 2H), 3.93 (t, 2H), 6.84 (d,2H), 7.12 (d, 2H).

Example 27(4) N-{(3-[4-(pentyloxy)phenyl]propyl}-β-alanine hydrochloride

TLC: Rf 0.24 (chloroform:methanol:aqueous ammonia=80:20:4);

¹H-NMR (CD₃OD): δ 0.94 (t, 3H), 1.41 (m, 4H), 1.72 (m, 2H), 1.96 (m,2H), 2.65 (t, 2H), 2.71 (t, 2H), 3.01 (m, 2H), 3.24 (t, 2H), 3.92 (t,2H), 6.84 (d, 2H), 7.12 (d, 2H).

Example 27(5) N-{3-[4-(hexyloxy)phenyl]propyl}-β-alanine hydrochloride

TLC: Rf 0.27 (chloroform:methanol:aqueous ammonia=80:20:4);

¹H-NMR (CD₃OD): δ 0.91 (m, 3H), 1.35 (m, 4H), 1.48 (m, 2H), 1.74 (m,2H), 1.96 (m, 2H), 2.65 (t, 2H), 2.71 (t, 2H), 3.01 (m, 2H), 3.24 (t,2H), 3.93 (t, 2H), 6.84 (d, 2H), 7.12 (d, 2H).

Example 27(6) N-{3-[4-(heptyloxy)phenyl]propyl}-β-alanine hydrochloride

TLC: Rf 0.29 (chloroform:methanol:aqueous ammonia=80:20:4);

¹H-NMR (CD₃OD): δ 0.90 (m, 3H), 1.32 (m, 8H), 1.72 (m, 2H), 1.96 (m,2H), 2.65 (t, 2H), 2.70 (t, 2H), 3.01 (m, 2H), 3.23 (t, 2H), 3.92 (t,2H), 6.84 (d, 2H), 7.12 (d, 2H).

Example 27(7) N-{3-[4-(octyloxy)phenyl]propyl}-β-alanine hydrochloride

TLC: Rf 0.30 (chloroform:methanol:aqueous ammonia=80:20:4);

¹H-NMR (CD₃OD): δ 0.90 (m, 3H), 1.31 (m, 10H), 1.74 (m, 2H), 1.96 (m,2H), 2.65 (t, 2H), 2.71 (t, 2H), 3.01 (m, 2H), 3.24 (t, 2H), 3.92 (t,2H), 6.84 (d, 2H), 7.12 (d, 2H).

Example 27(8) N-{3-[4-(nonyloxy)phenyl]propyl}-β-alanine hydrochloride

TLC: Rf 0.31 (chloroform:methanol:aqueous ammonia=80:20:4);

¹H-NMR (CD₃OD): δ 0.89 (m, 3H), 1.29 (m, 12H), 1.73 (m, 2H), 1.96 (m,2H), 2.65 (t, 2H), 2.71 (t, 2H), 3.01 (m, 2H), 3.24 (t, 2H), 3.92 (t,2H), 6.84 (d, 2H), 7.12 (d, 2H).

Example 27(9)N-(tert-butoxycarbonyl)-N-(3-{4-[(5-phenylpentyl)oxy]phenyl}propyl)-β-alanine

TLC: Rf 0.40 (chloroform:methanol=10:1);

¹H-NMR (CDCl₃): δ 1.45 (s, 9H), 1.67 (m, 8H), 2.53 (t, 2H), 2.64 (m,4H), 3.23 (t, 2H), 3.47 (t, 2H), 3.92 (t, 2H), 6.81 (d, 2H), 7.07 (d,2H), 7.18 (m, 2H), 7.27 (m, 3H).

Example 28N-{3-[4-(3-phenylpropoxy)phenyl]propyl}-N-(3-phenylpropyl)-β-alaninetrifluoroacetate

To a solution of tert-butylN{3-[4-(4-phenylbutoxy)phenyl]propyl}-β-alaninate (8.0 mg) indichloroethane (0.2 mL), 3-phenylpropanal (0.008 mL) and sodiumtriacetoxyborohydride (21 mg) were added and the mixture was shaken atroom temperature for 17 hours. Then, the reaction mixture was diluted byadding methanol (1.0 mL). After adding lanthanum toluenesulfonic acidresin (manufactured by MIMOTOPE; Cat No. MIL1025) (2 pins, 0.3 mmol),the mixture was allowed to stand for 1 hour. Then, the resin was takenout from the reaction mixture, washed with dichloromethane and methanoland then dipped in a 5% triethylamine-methanol solution (1.0 mL×2) for30 minutes. The obtained solutions were recovered, combined and thenconcentrated. To the residue, trifluoroacetic acid (1.0 mL) anddichloromethane (1.0 mL) were added, followed by stirring at roomtemperature for 16 hours and concentrated to thereby give the titlecompound (10 mg) having the following physical properties.

TLC: Rf 0.81 (ethyl acetate:acetic acid:water=3:1:1);

¹H-NMR (CD₃OD): δ 1.83-2.00 (m, 4H), 1.99-2.13 (m, 2H), 2.57-2.69 (m,4H), 2.70-2.84 (m, 4H), 3.04-3.20 (m, 4H), 3.40 (t, 2H), 3.91 (t, 2H),6.83 (d, 1H), 7.11 (d, 2H), 7.14-7.33 (m, 10H).

Example 293-({(2E)-3-[4-(3-phenylpropoxy)phenyl]-2-butenyl}amino)propanoic acidhydrochloride

To a suspension of 13-alanine (433 mg) in methanol (30 ml), sodiumhydroxide (204 mg) was added. Then, trimethoxymethane (532 111) wasadded to the mixture at 0° C. Further, a solution of(2E)-3-[4-(3-phenylpropoxy)phenyl]but-2-enal (1.43 g) in a mixture ofmethanol (30 ml) and tetrahydrofuran (10 ml) was added. The reactionmixture was stirred at 0° C. for 30 minutes. To the mixture, sodiumborohydride (221 mg) was added at 0° C. The reaction mixture was stirredat 0° C. for 30 minutes. After adding 2 N hydrochloric acid (5.5 ml),the reaction mixture was concentrated. To the residue thus obtained, amixed solvent of chloroform:methanol:aqueous ammonia=80:10:1 was added,followed by filtration. To the precipitate thus obtained, water wasadded and the mixture was centrifuged to give a precipitate. Theobtained residue was purified by silica gel column chromatography(chloroform:methanol:aqueous ammonia=80:20:4). To a suspension of thepurified product in dioxane (100 ml) and water (15 ml), a 4 mol/lhydrogen chloride-dioxane solution (0.9 ml) was added at 0° C. Thereaction mixture was concentrated and the residue was washed withdiethyl ether and dried to give the title compound (1.16 g) having thefollowing physical properties.

Melting point: 181-186° C.;

TLC: Rf 0.19 (chloroform:methanol:aqueous ammonia=80:20:4);

¹H-NMR (CD₃OD): δ 7.39 (d, J=9.00 Hz, 2H), 7.11-7.28 (m, 5H), 6.88 (d,J=9.00 Hz, 2H), 5.77 (tq, J=7.50, 1.50 Hz, 1H), 3.96 (t, J=6.50 Hz, 2H),3.88 (d, J=7.50 Hz, 2H), 3.30-3.34 (m, 2H), 2.74-2.83 (m, 4H), 2.15 (d,J=1.50 Hz, 3H), 2.00-2.11 (m, 2H).

Examples 29(1) to 29(4)

The procedure of Example 29 was similarly carried out, except for usinga corresponding aldehyde compound as a substitute for(2E)-3-[4-(3-phenylpropoxy)phenyl]but-2-enal and the corresponding aminecompound to thereby give invention compounds as shown below. In the caseof the compound of Example 29(4), the conversion into hydrochloride wasomitted.

Example 29(1)3-({(2E)-3-[4-(3-cyclohexylpropoxy)-2-methylphenyl]-2-propenyl}amino)propanoicacid hydrochloride

TLC: Rf 0.22 (chloroform:methanol:aqueous ammonia=80:20:4);

¹H-NMR (CD300D): δ 0.84-1.01 (m, 2H) 1.13-1.40 (m, 6H) 1.61-1.83 (m, 7H)2.34 (s, 3H) 2.77 (t, J=6.50 Hz, 2H) 3.22-3.29 (m, 2H) 3.82 (d, J=7.00Hz, 2H) 3.93 (t, J=6.50 Hz, 2H) 5.95-6.09 (m, 1H) 6.68-6.76 (m, 2H) 7.06(d, J=15.50 Hz, 1H) 7.43 (d, J=9.50 Hz, 1H).

Example 29(2)3-({[1-methyl-6-(4-phenylbutoxy)-3,4-dihydro-2-naphthalenyl]methyl}amino)propanoicacid hydrochloride

Melting point: 162.5-163.3° C.;

TLC: Rf 0.16 (chloroform:methanol:aqueous ammonia=80:20:4);

¹H-NMR (CD₃OD): δ 7.09-7.33 (m, 6H), 6.66-6.80 (m, 2H), 3.95-4.01 (m,2H), 3.93 (s, 2H), 3.25-3.34 (m, 2H), 2.71-2.83 (m, 4H), 2.61-2.71 (m,2H), 2.26-2.38 (m, 2H), 2.15 (s, 3H), 1.72-1.83 (m, 4H).

Example 29(3)1-{[1-methyl-6-(4-phenylbutoxy)-3,4-dihydro-2-naphthalenyl]methyl}-3-azetidinecarboxylicacid hydrochloride

TLC: Rf 0.14 (chloroform:methanol:aqueous ammonia=80:20:4);

¹H-NMR (CD₃OD): δ 7.03-7.39 (m, 6H), 6.64-6.82 (m, 2H), 4.20-4.48 (m,2H), 4.16 (s, 2H), 3.92-4.06 (m, 2H), 3.57-3.82 (m, 1H), 3.24-3.36 (m,2H), 2.61-2.79 (m, 4H), 2.17-2.29 (m, 5H), 1.72-1.83 (m, 4H);

Melting point: 121-122° C.

Example 29(4) N-{[1-(5-phenylpentyl)-1H-indol-5-yl]methyl}-β-alanine

TLC: Rf 0.23 (chloroform:methanol:aqueous ammonia=80:20:4);

¹H-NMR (CD₃OD): δ 7.66 (d, J=1.50 Hz, 1H), 7.46 (d, J=8.50 Hz, 1H),7.16-7.26 (m, 4H), 7.06-7.14 (m, 3H), 6.46 (d, J=3.00 Hz, 1H), 4.25 (s,2H), 4.18 (t, J=7.00 Hz, 2H), 3.15 (t, J=6.50 Hz, 2H), 2.53 (t, J=7.50Hz, 2H), 2.48 (t, J=6.50 Hz, 2H), 1.78-1.90 (m, 2H), 1.54-1.66 (m, 2H),1.23-1.36 (m, 2H).

Example 303-[4-[4-(3-phenylpropoxy)phenyl]-3,6-dihydropyridin-1(2H)-yl]propanoicacid trifluoroacetate

The procedures of Example 4 and Example 16 were followed in this orderbut using 4-[4-(3-phenylpropoxy)phenyl-1,2,3,6-tetrahydropyridine as asubstitute for 4-(3-aminopropyl)phenol to thereby give the titlecompound having the following physical properties.

TLC: Rf 0.24 (chloroform:methanol:aqueous ammonia=8:2:0.4);

¹H-NMR (CD₃OD): δ 7.40 (d, J=8.97 Hz, 2H), 7.10-7.30 (m, 5H), 6.90 (d,J=8.97 Hz, 2H), 5.92-6.09 (m, 1H), 3.96 (t, J=6.22 Hz, 2H), 3.89-4.00(m, 2H), 3.52 (t, J=7.04 Hz, 2H), 3.47-3.68 (m, 2H), 2.88 (t, J=7.04 Hz,2H), 2.83-2.92 (m, 2H), 2.79 (t, J=7.80 Hz, 2H), 1.97-2.14 (m, 2H).

Examples 31-01 to 31-94

The procedure of Example 29 was similarly carried out, except for usinga corresponding amine compound as a substitute for β-alanine and acorresponding aldehyde compound as a substitute for(2E)-3-[4-(3-phenylpropoxy)phenyl]but-2-enal to thereby give aninvention compound having the following physical properties.

Example 31-013-({(2E)-3-[3-methyl-4-(3-phenylpropoxy)phenyl]-2-propenyl}amino)propanoicacid hydrochloride

TLC: Rf 0.15 (chloroform:methanol:aqueous ammonia=80:20:4);

¹H-NMR (CD₃OD): δ 2.05-2.13 (m, 2H), 2.23 (s, 3H), 2.73-2.86 (m, 4H),3.24-3.29 (m, 2H), 3.79 (d, J=7.50 Hz, 2H), 3.97 (t, J=6.00 Hz, 2H),6.03-6.14 (m, 1H), 6.72-6.83 (m, 2H), 7.11-7.29 (m, 7H).

Example 31-023-({(2E)-3-[3-methyl-4-(4-phenylbutoxy)phenyl]-2-propenyl}amino)propanoicacid hydrochloride

TLC: Rf 0.16 (chloroform:methanol:aqueous ammonia=80:20:4);

¹H-NMR (CD₃OD): δ 1.78-1.86 (m, 4H), 2.19 (s, 3H), 2.64-2.79 (m, 4H),3.23-3.28 (m, 2H), 3.78 (d, J=7.00 Hz, 2H), 3.96-4.03 (m, 2H), 6.03-6.14(m, 1H), 6.76 (d, J=15.50 Hz, 1H), 6.83 (d, J=8.00 Hz, 1H), 7.09-7.28(m, 7H).

Example 31-033-[((2E)-3-{3-methyl-4-[(5-phenylpentyl)oxy]phenyl}-2-propenyl)amino]propanoicacid hydrochloride

TLC: Rf 0.18 (chloroform:methanol:aqueous ammonia=80:20:4);

¹H-NMR (CD₃OD): δ 1.48-1.58 (m, 2H), 1.65-1.75 (m, 2H), 1.77-1.87 (m,2H), 2.15 (s, 3H), 2.64 (t, J=7.50 Hz, 2H), 2.75 (t, J=6.50 Hz, 2H),3.19-3.28 (m, 2H), 3.78 (d, J=7.50 Hz, 2H), 3.97 (t, J=6.00 Hz, 2H),6.02-6.14 (m, 1H), 6.76 (d, J=16.00 Hz, 1H), 6.83 (d, J=8.00 Hz, 1H),7.08-7.27 (m, 7H).

Example 31-043-({(2E)-3-[4-(4-phenylbutoxy)phenyl]-2-butenyl}amino)propanoic acidhydrochloride

TLC: Rf 0.20 (chloroform:methanol:aqueous ammonia=80:20:4);

¹H-NMR (CD₃OD): δ 1.76-1.82 (m, 4H), 2.14 (d, J=1.50 Hz, 3H), 2.64-2.71(m, 2H), 2.76 (t, J=6.50 Hz, 2H), 3.30-3.35 (m, 2H), 3.87 (d, J=7.50 Hz,2H), 3.96-4.01 (m, 2H), 5.75 (tq, J=7.50, 1.50 Hz, 1H), 6.88 (d, J=9.00Hz, 2H), 7.09-7.28 (m, 5H), 7.38 (d, J=9.00 Hz, 2H).

Example 31-053-[((2E)-3-{4-[(5-phenylpentyl)oxy]phenyl}-2-butenyl)amino]propanoicacid hydrochloride

TLC: Rf 0.20 (chloroform:methanol:aqueous ammonia=80:20:4);

¹H-NMR (CD₃OD): δ 1.45-1.56 (m, 2H), 1.63-1.74 (m, 2H), 1.74-1.85 (m,2H), 2.15 (d, J=1.50 Hz, 3H), 2.63 (t, J=7.50 Hz, 2H), 2.76 (t, J=6.50Hz, 2H), 3.31-3.37 (m, 2H), 3.87 (d, J=7.50 Hz, 2H), 3.96 (t, J=6.50 Hz,2H), 5.75 (tq, J=7.50, 1.50 Hz, 1H), 6.87 (d, J=9.00 Hz, 2H), 7.10-7.26(m, 5H), 7.38 (d, J=9.00 Hz, 2H).

Example 31-063-({[6-(4-phenylbutoxy)-3,4-dihydro-2-naphthalenyl]methyl}amino)propanoicacid hydrochloride

TLC: Rf 0.19 (chloroform:methanol:aqueous ammonia=80:20:4);

¹H-NMR (CD₃OD): δ 1.75-1.82 (m, 4H) 2.34 (t, J=8.00 Hz, 2H) 2.63-2.71(m, 2H) 2.77 (t, J=6.50 Hz, 2H) 2.85 (t, J=8.00 Hz, 2H) 3.23-3.28 (m,2H) 3.79 (s, 2H) 3.97 (t, J=6.00 Hz, 2H) 6.62 (s, 1H) 6.68-6.73 (m, 2H)7.00 (d, J=7.50 Hz, 1H) 7.11-7.28 (m, 5H).

Example 31-073-({[6-(4-phenylbutoxy)-3,4-dihydro-2-naphthalenyl]methyl}amino)butanoicacid hydrochloride

TLC: Rf 0.32 (chloroform:methanol:aqueous ammonia=80:20:4);

¹H-NMR (CD₃OD): δ 1.42 (d, J=7.00 Hz, 3H) 1.75-1.81 (m, 4H) 2.29-2.44(m, 2H) 2.64-2.71 (m, 2H) 2.73-2.78 (m, 2H) 2.86 (t, J=8.00 Hz, 2H)3.61-3.72 (m, 1H) 3.82 (s, 2H) 3.97 (t, J=6.00 Hz, 2H) 6.64 (s, 1H)6.68-6.73 (m, 2H) 7.00 (d, J=7.50 Hz, 1H) 7.11-7.28 (m, 5H).

Example 31-082-methyl-3-({[6-(4-phenylbutoxy)-3,4-dihydro-2-naphthalenyl]methyl}amino)propanoicacid hydrochloride

TLC: Rf 0.29 (chloroform:methanol:aqueous ammonia=80:20:4);

¹H-NMR (CD₃OD): δ 1.30 (d, J=7.00 Hz, 3H) 1.73-1.82 (m, 4H) 2.33 (t,J=7.50 Hz, 2H) 2.63-2.71 (m, 2H) 2.81-2.95 (m, 3H) 3.06 (dd, J=13.00,4.50 Hz, 1H) 3.21-3.29 (m, 1H) 3.79 (s, 2H) 3.97 (t, J=6.00 Hz, 2H) 6.62(s, 1H) 6.68-6.74 (m, 2H) 7.01 (d, J=8.00 Hz, 1H) 7.10-7.28 (m, 5H).

Example 31-092-fluoro-3-({[6-(4-phenylbutoxy)-3,4-dihydro-2-naphthalenyl]methyl}amino)propanoicacid hydrochloride

TLC: Rf 0.16 (chloroform:methanol:aqueous ammonia=80:20:4);

¹H-NMR (CD₃OD): δ 1.74-1.82 (m, 4H) 2.35 (t, J=8.00 Hz, 2H) 2.64-2.71(m, 2H) 2.86 (t, J=8.00 Hz, 2H) 3.47-3.72 (m, 2H) 3.85 (s, 2H) 3.97 (t,J=6.00 Hz, 2H) 5.36 (ddd, J=48.50, 8.00, 3.50 Hz, 1H) 6.64 (s, 1H)6.67-6.76 (m, 2H) 7.01 (d, J=800 Hz, 1H) 7.10-7.30 (m, 5H).

Example 31-103-({(2E)-3-[2-methyl-4-(4-phenylbutoxy)phenyl]-2-propenyl}amino)propanoicacid hydrochloride

TLC: Rf 0.22 (chloroform:methanol:aqueous ammonia=80:20:4);

¹H-NMR (CD₃OD): δ 1.72-1.83 (m, 4H) 2.34 (s, 3H) 2.64-2.71 (m, 2H) 2.77(t, J=6.50 Hz, 2H) 3.23-3.29 (m, 2H) 3.82 (d, J=7.00 Hz, 2H) 3.96 (t,J=6.00 Hz, 2H) 5.96-6.08 (m, 1H) 6.70-6.75 (m, 2H) 7.06 (d, J=15.50 Hz,1H) 7.09-7.28 (m, 5H) 7.42 (d, J=9.50 Hz, 1H).

Example 31-113-({(2E)-3-[4-(4-cyclohexylbutoxy)-2-methylphenyl]-2-propenyl}amino)propanoicacid hydrochloride

TLC: Rf 0.23 (chloroform:methanol:aqueous ammonia=80:20:4);

¹H-NMR (CD₃OD): δ 0.81-1.00 (m, 2H) 1.13-1.35 (m, 6H) 1.41-1.54 (m, 2H)1.62-1.80 (m, 7H) 2.34 (s, 3H) 2.77 (t, J=6.50 Hz, 2H) 3.24-3.29 (m, 2H)3.82 (d, J=7.50 Hz, 2H) 3.95 (t, J=6.50 Hz, 2H) 5.95-6.10 (m, 1H)6.70-6.76 (m, 2H) 7.06 (d, J=15.50 Hz, 1H) 7.43 (d, J=9.00 Hz, 1H).

Example 31-123-({(2E)-3-[4-(4-phenylbutoxy)phenyl]-2-propenyl}amino)propanoic acidhydrochloride

TLC: Rf 0.29 (chloroform:methanol:aqueous ammonia=80:20:4);

¹H-NMR (CD₃OD): δ 7.39 (d, J=8.79 Hz, 2H) 7.09-7.30 (m, 5H) 6.89 (d,J=8.79 Hz, 2H) 6.80 (d, J=16.11 Hz, 1H) 6.10 (dt, J=16.11, 7.32 Hz, 1H)3.92-4.04 (m, 2H) 3.79 (dd, J=7.32, 1.01 Hz, 2H) 3.24-3.29 (m, 2H) 2.75(t, J=6.59 Hz, 2H) 2.60-2.71 (m, 2H) 1.71-1.86 (m, 4H).

Example 31-133-[((2E)-3-{4-[3-(4-chlorophenyl)propoxy]phenyl}-2-propenyl)amino]propanoicacid hydrochloride

TLC: Rf 0.28 (chloroform:methanol:aqueous ammonia=80:20:4);

¹H-NMR (CD₃OD): δ 7.40 (d, J=8.79 Hz, 2H) 7.25 (d, J=8.60 Hz, 2H) 7.19(d, J=8.60 Hz, 2H) 6.89 (d, J=8.79 Hz, 2H) 6.81 (d, J=15.74 Hz, 1H) 6.11(dt, J=15.74, 7.14 Hz, 1H) 3.96 (t, J=6.13 Hz, 2H) 3.79 (d, J=7.14 Hz,2H) 3.20-3.29 (m, 2H) 2.69-2.84 (m, 4H) 1.98-2.11 (m, 2H).

Example 31-143-[((2E)-3-{4-[(4-methylpentyl)oxy]phenyl}-2-propenyl)amino]propanoicacid hydrochloride

TLC: Rf 0.27 (chloroform:methanol:aqueous ammonia=80:20:4);

¹H-NMR (CD₃OD): δ 7.40 (d, J=8.79 Hz, 2H) 6.89 (d, J=8.79 Hz, 2H) 6.81(d, J=15.74 Hz, 1H) 6.11 (dt, J=15.74, 7.32 Hz, 1H) 3.96 (t, J=6.50 Hz,2H) 3.80 (d, J=7.32 Hz, 2H) 3.22-3.29 (m, 2H) 2.75 (t, J=6.59 Hz, 2H)1.70-1.84 (m, 2H) 1.51-1.68 (m, 1H) 1.28-1.43 (m, 2H) 0.93 (d, J=6.59Hz, 6H).

Example 31-153-[((2E)-3-{2-chloro-4-[(5-phenylpentyl)oxy]phenyl}-2-propenyl)amino]propanoicacid hydrochloride

TLC: Rf 0.29 (chloroform:methanol:aqueous ammonia=80:20:4);

¹H-NMR (CD₃OD): δ 7.59 (d, J=8.79 Hz, 1H) 7.08-7.28 (m, 6H) 6.95 (d,J=2.56 Hz, 1H) 6.87 (dd, J=8.79, 2.56 Hz, 1H) 6.18 (dt, J=15.70, 7.16Hz, 1H) 3.97 (t, J=6.41 Hz, 2H) 3.85 (dd, J=7.16, 1.01 Hz, 2H) 3.25-3.34(m, 2H) 2.77 (t, J=6.59 Hz, 2H) 2.63 (t, J=7.69 Hz, 2H) 1.74-1.87 (m,2H) 1.61-1.74 (m, 2H) 1.41-1.57 (m, 2H).

Example 31-163-({(2E)-3-[2-chloro-4-(4-phenylbutoxy)phenyl]-2-propenyl}amino)propanoicacid hydrochloride

TLC: Rf 0.29 (chloroform:methanol:aqueous ammonia=80:20:4);

¹H-NMR (CD₃OD): δ 7.58 (d, J=8.79 Hz, 1H) 7.08-7.31 (m, 6H) 6.96 (d,J=2.56 Hz, 1H) 6.88 (dd, J=8.79, 2.56 Hz, 1H) 6.18 (dt, J=15.84, 7.19Hz, 1H) 3.93-4.04 (m, 2H) 3.85 (dd, J=7.19, 1.10 Hz, 2H) 3.25-3.33 (m,2H) 2.77 (t, J=6.59 Hz, 2H) 2.62-2.72 (m, 2H) 1.74-1.84 (m, 4H).

Example 31-173-[((2E)-3-{2-chloro-4-[3-(4-chlorophenyl)propoxy]phenyl}-2-propenyl)amino]propanoicacid hydrochloride

TLC: Rf 0.29 (chloroform:methanol:aqueous ammonia=80:20:4);

¹H-NMR (CD₃OD): δ 7.59 (d, J=8.79 Hz, 1H) 7.12-7.31 (m, 5H) 6.96 (d,J=2.56 Hz, 1H) 6.88 (dd, J=8.79, 2.56 Hz, 1H) 6.18 (dt, J=15.74, 7.32Hz, 1H) 3.97 (t, J=6.22 Hz, 2H) 3.85 (dd, J=7.32, 1.10 Hz, 2H) 3.26-3.34(m, 2H) 2.71-2.84 (m, 4H) 1.96-2.14 (m, 2H);

Melting point: 119-124° C.

Example 31-18 3-({[6-(3-phenylpropoxy)-2-naphthyl]methyl}amino)propanoicacid

TLC: Rf 0.13 (chloroform:methanol:aqueous ammonia=80:20:4);

¹H-NMR (CDCl₃+CD₃OD=5:1): δ 2.19 (m, 2H) 2.47 (t, J=6.00 Hz, 2H) 2.87(m, 2H) 3.10 (t, J=6.00 Hz, 2H) 4.10 (t, J=6.50 Hz, 2H) 4.22 (s, 2H)7.12 (d, J=2.00 Hz, 1H) 7.26 (m, 6H) 7.43 (dd, J=8.50, 2.00 Hz, 1H) 7.79(m, 3H).

Example 31-193-[((2E)-3-{4-[(4-tert-butylbenzyl)oxy]-2-chlorophenyl}-2-propenyl)amino]propanoicacid hydrochloride

TLC: Rf 0.40 (n-butanol:acetic acid:water=20:4:1);

¹H-NMR (CD₃OD): δ 7.61 (d, J=8.78 Hz, 1H) 7.41 (d, J=8.70 Hz, 2H) 7.34(d, J=8.70 Hz, 2H) 7.17 (d, J=15.92 Hz, 1H) 7.05 (d, J=2.56 Hz, 1H) 6.96(dd, J=8.78, 2.56 Hz, 1H) 6.21 (dt, J=15.92, 7.25 Hz, 1H) 5.06 (s, 2H)3.86 (dd, J=7.25, 0.82 Hz, 2H) 3.25-3.35 (m, 2H) 2.78 (t, J=6.68 Hz, 2H)1.31 (s, 9H).

Example 31-203-({(2E)-3-[4-(1,1′-biphenyl-4-ylmethoxy)-2-chlorophenyl]-2-propenyl}amino)propanoicacid hydrochloride

TLC: Rf 0.41 (n-butanol:acetic acid:water=20:4:1);

¹H-NMR (CD₃OD): δ 7.57-7.67 (m, 5H) 7.50 (d, J=8.40 Hz, 2H) 7.39-7.46(m, 2H) 7.29-7.37 (m, 1H) 7.19 (d, J=15.73 Hz, 1H) 7.10 (d, J=2.38 Hz,1H) 7.00 (dd, J=8.78, 2.38 Hz, 1H) 6.19 (dt, J=15.73, 7.25 Hz, 1H) 5.16(s, 2H) 3.85 (dd, J=7.25, 1.10 Hz, 2H) 3.26-3.36 (m, 2H) 2.76 (t, J=6.59Hz, 2H).

Example 31-213-[((2E)-3-{2-chloro-4-[3-(2-fluorophenyl)propoxy]phenyl}-2-propenyl)amino]propanoicacid hydrochloride

TLC: Rf 0.39 (n-butanol:acetic acid:water=20:4:1);

¹H-NMR (CD₃OD): δ 7.61 (d, J=8.78 Hz, 1H) 7.12-7.30 (m, 3H) 6.96-7.13(m, 2H) 6.95 (d, J=2.38 Hz, 1H) 6.88 (dd, J=8.60, 2.38 Hz, 1H) 6.21 (dt,J=15.74, 7.32 Hz, 1H) 3.99 (t, J=6.13 Hz, 2H) 3.86 (dd, J=7.32, 1.10 Hz,2H) 3.27-3.36 (m, 2H) 2.75-2.88 (m, 4H) 2.00-2.13 (m, 2H).

Example 31-221-{[6-(4-phenylbutoxy)-3,4-dihydro-2-naphthalenyl]methyl}-β-azetidinecarboxylicacid hydrochloride

TLC: Rf 0.11 (chloroform:methanol:aqueous ammonia=80:20:4);

¹H-NMR (CD₃OD): δ 1.75-1.80 (m, 4H), 2.27 (t, J=8.00 Hz, 2H), 2.63-2.71(m, 2H), 2.82 (t, J=8.00 Hz, 2H), 3.64-3.78 (m, 1H), 3.93-4.01 (m, 4H),4.16-4.46 (m, 4H), 6.62 (s, 1H), 6.68-6.72 (m, 2H), 7.03 (d, J=9.00 Hz,1H), 7.10-7.27 (m, 5H);

Melting point: 152-155° C.

Example 31-233-({(2E)-3-[2-methoxy-4-(3-phenylpropoxy)phenyl]-2-propenyl}amino)propanoicacid hydrochloride

TLC: Rf 0.27 (n-butanol:acetic acid:water=20:4:1);

¹H-NMR (CD₃OD): δ 7.36 (d, J=8.4 Hz, 1H), 7.11-7.30 (m, 5H), 7.03 (d,J=16.1 Hz, 1H), 6.35-6.62 (m, 2H), 6.05-6.26 (m, 1H), 3.89-4.06 (m, 2H),3.64-3.89 (m, 5H), 3.15-3.37 (m, 2H), 2.65-2.89 (m, 4H), 1.94-2.16 (m,2H).

Example 31-243-({(2E)-3-[2-methoxy-4-(4-phenylbutoxy)phenyl]-2-propenyl}amino)propanoicacid hydrochloride

TLC: Rf 0.28 (n-butanol:acetic acid:water=20:4:1);

¹H-NMR (CD₃OD): δ 7.36 (d, J=8.23 Hz, 2H) 7.09-7.30 (m, 5H) 7.02 (d,J=16.28 Hz, 1H) 3.88-4.07 (m, 2H) 3.62-3.88 (m, 5H) 3.16-3.40 (m, 2H)2.46-2.85 (m, 4H) 1.71-1.87 (m, 4H).

Example 31-253-[((2E)-3-{2-methoxy-4-[(5-phenylpentyl)oxy]phenyl}-2-propenyl)amino]propanoicacid hydrochloride

TLC: Rf 0.30 (n-butanol:acetic acid:water=20:4:1);

¹H-NMR (CD₃OD): δ 7.36 (d, J=8.4 Hz, 1H), 7.09-7.29 (m, 5H), 7.02 (d,J=15.9 Hz, 1H), 6.41-6.58 (m, 2H), 6.04-6.30 (m, 1H), 3.98 (t, J=6.4 Hz,2H), 3.67-3.89 (m, 5H), 3.05-3.43 (m, 2H), 2.74 (t, J=6.6 Hz, 2H),2.54-2.71 (m, 2H), 1.76-1.88 (m, 2H), 1.60-1.76 (m, 2H), 1.42-1.59 (m,2H).

Example 31-263-{[(6-{3-[3,5-bis(trifluoromethyl)phenyl]propoxy}-2-naphthyl)methyl]amino}propanoicacid hydrochloride

TLC: Rf 0.16 (chloroform:methanol:acetic acid=9:1:0.5);

¹H-NMR (CD₃OD): δ 7.73-7.97 (m, 6H) 7.52 (dd, J=8.32, 1.56 Hz, 1H) 7.25(d, J=2.47 Hz, 1H) 7.19 (dd, J=8.87, 2.47 Hz, 1H) 4.37 (s, 2H) 4.14 (t,J=5.95 Hz, 2H) 3.28-3.37 (m, 2H) 3.01-3.13 (m, 2H) 2.71-2.86 (m, 2H)2.15-2.31 (m, 2H).

Example 31-273-[({6-[3-(2-chlorophenyl)propoxy]-2-naphthyl}methyl)amino]propanoicacid acetate

TLC: Rf 0.17 (chloroform:methanol:acetic acid=9:1:0.5);

¹H-NMR (CD₃OD): δ 7.89 (s, 1H) 7.82 (d, J=8.42 Hz, 1H) 7.80 (d, J=8.42Hz, 1H) 7.49 (dd, J=8.60, 1.65 Hz, 1H) 7.33-7.39 (m, 1H) 7.27-7.33 (m,1H) 7.11-7.26 (m, 4H) 4.31 (s, 2H) 4.12 (t, J=6.13 Hz, 2H) 3.20 (t,J=6.22 Hz, 2H) 2.92-3.04 (m, 2H) 2.52 (t, J=6.22 Hz, 2H) 2.08-2.24 (m,2H) 1.95 (s, 3H).

Example 31-283-[({6-[3-(2,6-dichlorophenyl)propoxy]-2-naphthyl}methyl)amino]propanoicacid acetate

TLC: Rf 0.17 (chloroform:methanol:acetic acid=9:1:0.5);

¹H-NMR (CD₃OD): δ 7.89 (s, 1H) 7.83 (d, J=8.50 Hz, 1H) 7.80 (d, J=8.50Hz, 1H) 7.50 (dd, J=8.42, 1.46 Hz, 1H) 7.35 (d, J=8.50 Hz, 2H) 7.25 (d,J=2.38 Hz, 1H) 7.14-7.21 (m, 2H) 4.32 (s, 2H) 4.19 (t, J=6.04 Hz, 2H)3.15-3.25 (m, 4H) 2.49-2.57 (m, 2H) 2.08-2.20 (m, 2H) 1.93 (s, 3H).

Example 31-293-({(2Z)-3-[4-(3-phenylpropoxy)phenyl]-2-butenyl}amino)propanoic acidhydrochloride

TLC: Rf 0.27 (chloroform:methanol:aqueous ammonia=80:20:4);

¹H-NMR (CD₃OD): δ 7.10-7.29 (m, 7H), 6.94 (d, J=9.00 Hz, 2H), 5.55 (tq,J=7.00, 1.50 Hz, 1H), 3.97 (t, J=6.00 Hz, 2H), 3.63 (dd, J=7.00, 1.00Hz, 2H), 3.12 (t, J=6.50 Hz, 2H), 2.80 (t, J=7.50 Hz, 2H), 2.62 (t,J=6.50 Hz, 2H), 2.12-2.15 (m, 3H), 2.02-2.11 (m, 2H).

Example 31-303-[((2E)-3-{2-chloro-4-[(4-propylbenzyl)oxy]phenyl}-2-propenyl)amino]propanoicacid hydrochloride

TLC: Rf 0.25 (n-butanol:acetic acid:water=20:4:1);

¹H-NMR (CD₃OD): δ 7.59 (d, J=9.0 Hz, 1H), 7.32 (d, J=8.1 Hz, 2H),7.14-7.23 (m, 3H), 7.06 (d, J=2.6 Hz, 1H), 6.96 (dd, J=8.8, 2.6 Hz, 1H),6.18 (dt, J=9.0, 8.8 Hz, 1H), 5.06 (s, 2H), 3.85 (dd, J=7.3, 0.9 Hz,2H), 3.26-3.34 (m, 2H), 2.76 (t, J=6.6 Hz, 2H), 2.55-2.63 (m, 2H),1.56-1.71 (m, 2H), 0.93 (t, J=7.3 Hz, 3H).

Example 31-313-[((2E)-3-{2-chloro-4-[(4-pentylbenzyl)oxy]phenyl}-2-propenyl)amino]propanoicacid hydrochloride

TLC: Rf 0.22 (n-butanol:acetic acid:water=20:4:1);

¹H-NMR (CD₃OD): δ 7.60 (d, J=8.78 Hz, 1H) 7.32 (d, J=8.23 Hz, 2H)7.12-7.23 (m, 3H) 7.06 (d, J=2.56 Hz, 1H) 6.96 (dd, J=8.60, 2.56 Hz, 1H)6.09-6.31 (m, 1H) 5.06 (s, 2H) 3.85 (dd, J=7.23, 1.01 Hz, 2H) 3.22-3.39(m, 2H) 2.76 (t, J=6.59 Hz, 2H) 2.61 (t, J=8.10 Hz, 2H) 1.54-1.68 (m,2H) 1.25-1.42 (m, 4H) 0.89 (t, J=6.90 Hz, 3H).

Example 31-323-[((2E)-3-{2-chloro-4-[(4-hexylbenzyl)oxy]phenyl}-2-propenyl)amino]propanoicacid hydrochloride

TLC: Rf 0.25 (n-butanol:acetic acid:water=20:4:1);

¹H-NMR (CD₃OD): δ 7.59 (d, J=8.8 Hz, 1H), 7.32 (d, J=8.1 Hz, 2H),7.11-7.25 (m, 3H), 7.06 (d, J=2.6 Hz, 1H), 6.96 (dd, J=8.8, 2.6 Hz, 1H),6.06-6.30 (m, 1H), 5.06 (s, 2H), 3.85 (dd, J=7.2, 1.0 Hz, 2H), 3.19-3.40(m, 2H), 2.76 (t, J=6.3 Hz, 2H), 2.54-2.66 (m, 2H), 1.50-1.69 (m, 2H),1.26-1.38 (m, 6H), 0.83-0.93 (m, 3H).

Example 31-333-[((2E)-3-{2-chloro-4-[(4-cyclohexylbenzyl)oxy]phenyl}-2-propenyl)amino]propanoicacid hydrochloride

TLC: Rf 0.22 (n-butanol:acetic acid:water=20:4:1);

¹H-NMR (CD₃OD): δ 7.59 (d, J=8.6 Hz, 1H), 7.32 (d, J=8.4 Hz, 2H),7.13-7.25 (m, 3H), 7.06 (d, J=2.6 Hz, 1H), 6.96 (dd, J=8.9, 2.6 Hz, 1H),6.04-6.30 (m, 1H), 5.06 (s, 2H), 3.84 (d, J=6.6 Hz, 2H), 2.70-2.79 (m,2H), 2.42-2.58 (m, 2H), 1.69-1.89 (m, 5H), 1.20-1.52 (m, 6H).

Example 31-343-[((2E)-3-{2-chloro-4-[(4-isobutylbenzyl)oxy]phenyl}-2-propenyl)amino]propanoicacid hydrochloride

TLC: Rf 0.24 (n-butanol:acetic acid:water=20:4:1);

¹H-NMR (CD₃OD): δ 7.60 (d, J=8.6 Hz, 1H), 7.32 (d, J=8.2 Hz, 2H),7.12-7.25 (m, 3H), 7.07 (d, J=2.6 Hz, 1H), 6.97 (dd, J=9.0, 2.6 Hz, 1H),6.18 (dt, J=15.6, 7.2 Hz, 1H), 5.06 (s, 2H), 3.85 (dd, J=7.2, 1.2 Hz,2H), 3.25-3.35 (m, 2H), 2.75 (t, J=6.5 Hz, 2H), 2.48 (d, J=7.3 Hz, 2H),1.76-1.95 (m, 1H), 0.89 (d, J=6.6 Hz, 6H).

Example 31-353-[((2E)-3-{4-[2-(1,1′-biphenyl-4-yl)ethoxy]-2-chlorophenyl}-2-propenyl)amino]propanoicacid hydrochloride

TLC: Rf 0.25 (n-butanol:acetic acid:water=20:4:1);

¹H-NMR (CD₃OD): δ 7.48-7.68 (m, 5H) 7.24-7.47 (m, 4H) 7.18 (d, J=15.92Hz, 1H) 6.99 (d, J=2.56 Hz, 1H) 6.91 (dd, J=8.69, 2.56 Hz, 1H) 6.05-6.28(m, 1H) 4.25 (t, J=6.68 Hz, 2H) 3.85 (dd, J=7.32, 1.10 Hz, 2H) 3.20-3.39(m, 2H) 3.11 (t, J=6.68 Hz, 2H) 2.76 (t, J=6.68 Hz, 2H).

Example 31-363-[((2E)-3-({4-[(4-butylbenzyl)oxy]-2-chlorophenyl}-2-propenyl)amino]propanoicacid hydrochloride

TLC: Rf 0.20 (n-butanol:acetic acid:water=20:4:1);

¹H-NMR (CD₃OD): δ 7.60 (d, J=8.8 Hz, 1H), 7.32 (d, J=8.4 Hz, 2H),7.11-7.24 (m, 3H), 7.06 (d, J=2.6 Hz, 1H), 6.96 (dd, J=8.8, 2.3 Hz, 1H),6.18 (dt, J=15.9, 7.1 Hz, 1H), 5.06 (s, 2H), 3.85 (dd, J=7.1, 1.1 Hz,2H), 3.24-3.38 (m, 2H), 2.76 (t, J=6.6 Hz, 2H), 2.61 (t, J=7.8 Hz, 2H),1.50-1.68 (m, 2H), 1.25-1.43 (m, 2H), 0.93 (t, J=7.3 Hz, 3H).

Example 31-373-{[(2E)-3-(2-chloro-4-{3-[4-(trifluoromethyl)phenyl]propoxy}phenyl)-2-propenyl]amino}propanoicacid hydrochloride

TLC: Rf 0.19 (n-butanol:acetic acid:water=20:4:1);

¹H-NMR (CD₃OD): δ 7.49-7.67 (m, 3H), 7.41 (d, J=8.2 Hz, 2H), 7.18 (d,J=15.7 Hz, 1H), 6.97 (d, J=2.6 Hz, 1H), 6.89 (dd, J=8.8, 2.6 Hz, 1H),6.07-6.29 (m, 1H), 4.00 (t, J=6.1 Hz, 2H), 3.85 (d, J=7.2 Hz, 2H),3.17-3.41 (m, 2H), 2.89 (dd, J=8.1, 7.3 Hz, 2H), 2.68-2.82 (m, 2H),2.01-2.19 (m, 2H).

Example 31-383-({[1-methyl-6-(3-phenylpropoxy)-3,4-dihydro-2-naphthalenyl]methyl}amino)propanoicacid hydrochloride

TLC: Rf 0.25 (chloroform:methanol:aqueous ammonia=80:20:4);

¹H-NMR (CD₃OD): δ 7.31 (d, J=8.50 Hz, 1H), 7.11-7.28 (m, 5H), 6.71-6.79(m, 2H), 3.92-3.99 (m, 4H), 3.27-3.33 (m, 2H), 2.73-2.82 (m, 6H), 2.33(t, J=7.00 Hz, 2H), 2.16 (s, 3H), 2.01-2.11 (m, 2H).

Example 31-391-{[1-methyl-6-(3-phenylpropoxy)-3,4-dihydro-2-naphthalenyl]methyl}-3-azetidinecarboxylicacid hydrochloride

TLC: Rf 0.20 (chloroform:methanol:aqueous ammonia=80:20:4);

¹H-NMR (CD₃OD): δ 7.32 (d, J=8.50 Hz, 1H), 7.11-7.28 (m, 5H), 6.76 (dd,J=8.50, 2.50 Hz, 1H), 6.72 (d, J=2.50 Hz, 1H), 4.20-4.45 (m, 4H), 4.16(s, 2H), 3.96 (t, J=6.50 Hz, 2H), 3.67-3.78 (m, 1H), 2.69-2.83 (m, 4H),2.20-2.29 (m, 5H), 2.01-2.11 (m, 2H).

Example 31-403-({[6-(4-phenylbutoxy)-1H-inden-2-yl]methyl}amino)propanoic acid

TLC: Rf 0.24 (chloroform:methanol:aqueous ammonia=80:20:4);

¹H-NMR (CD₃OD): δ 7.04-7.33 (m, 7H), 6.92-6.97 (m, 1H), 6.74-6.84 (m,1H), 4.03-4.10 (m, 2H), 3.96-4.02 (m, 2H), 3.44-3.52 (m, 2H), 3.14-3.21(m, 2H), 2.63-2.72 (m, 2H), 2.46-2.54 (m, 2H), 1.75-1.83 (m, 4H).

Example 31-413-({(2E)-2-methyl-3-[4-(3-phenylpropoxy)phenyl]-2-propenyl}amino)propanoicacid hydrochloride

TLC: Rf 0.27 (chloroform:methanol:aqueous ammonia=80:20:4);

¹H-NMR (CD₃OD): δ 7.12-7.29 (m, 7H), 6.91 (d, J=8.50 Hz, 2H), 6.65-6.68(m, 1H), 3.97 (t, J=6.00 Hz, 2H), 3.77 (s, 2H), 3.25-3.30 (m, 2H),2.75-2.85 (m, 4H), 2.01-2.12 (m, 2H), 2.00 (d, J=1.00 Hz, 3H).

Example 31-423-({(2E)-2-methyl-3-[4-(4-phenylbutoxy)phenyl]-2-propenyl}amino)propanoicacid hydrochloride

TLC: Rf 0.27 (chloroform:methanol:aqueous ammonia=80:20:4);

¹H-NMR (CD₃OD): δ 7.10-7.29 (m, 7H), 6.91 (d, J=8.50 Hz, 2H), 6.64-6.67(m, 1H), 3.97-4.02 (m, 2H), 3.76 (s, 2H), 3.25-3.29 (m, 2H), 2.78 (t,J=6.50 Hz, 2H), 2.64-2.71 (m, 2H), 2.00 (d, J=1.00 Hz, 3H), 1.76-1.82(m, 4H).

Example 31-433-[({6-[3-(4-chlorophenyl)propoxy]-1-methyl-3,4-dihydro-2-naphthalenyl}methyl)amino]propanoicacid hydrochloride

TLC: Rf 0.30 (chloroform:methanol:aqueous ammonia=80:20:4);

¹H-NMR (CD₃OD): δ 7.31 (d, J=8.50 Hz, 1H), 7.25 (d, J=8.50 Hz, 2H), 7.19(d, J=8.50 Hz, 2H), 6.75 (dd, J=8.50, 2.50 Hz, 1H), 6.72 (d, J=2.50 Hz,1H), 3.91-3.99 (m, 4H), 3.27-3.34 (m, 2H), 2.73-2.82 (m, 6H), 2.29-2.38(m, 2H), 2.16 (t, J=1.5 Hz, 3H), 2.00-2.11 (m, 2H).

Example 31-441-({6-[3-(4-chlorophenyl)propoxy]-1-methyl-3,4-dihydro-2-naphthalenyl}methyl)-3-azetidinecarboxylicacid hydrochloride

TLC: Rf 0.22 (chloroform:methanol:aqueous ammonia=80:20:4);

¹H-NMR (CD₃OD): δ 7.32 (d, J=8.50 Hz, 1H), 7.25 (d, J=8.50 Hz, 2H), 7.19(d, J=8.50 Hz, 2H), 6.76 (dd, J=8.50, 2.50 Hz, 1H), 6.71 (d, J=2.50 Hz,1H), 4.15-4.47 (m, 6H), 3.96 (t, J=6.00 Hz, 2H), 3.65-3.80 (m, 1H),2.69-2.82 (m, 4H), 2.20-2.29 (m, 5H), 1.99-2.11 (m, 2H);

Melting point: 147-150° C.

Example 31-453-({[6-(3-cyclohexylpropoxy)-1-methyl-3,4-dihydro-2-naphthalenyl]methyl}amino)propanoicacid hydrochloride

TLC: Rf 0.30 (chloroform:methanol:aqueous ammonia=80:20:4);

¹H-NMR (CD₃OD): δ 7.30 (d, J=8.50 Hz, 1H), 6.71-6.78 (m, 2H), 3.90-3.98(m, 4H), 3.26-3.34 (m, 2H), 2.73-2.82 (m, 4H), 2.29-2.37 (m, 2H), 2.16(t, J=1.50 Hz, 3H), 1.61-1.83 (m, 7H), 1.12-1.40 (m, 6-H), 0.84-1.01 (m,2H).

Example 31-461-{[6-(3-cyclohexylpropoxy)-1-methyl-3,4-dihydro-2-naphthalenyl]methyl}-3-azetidinecarboxylicacid hydrochloride

TLC: Rf 0.22 (chloroform:methanol:aqueous ammonia=80:20:4);

¹H-NMR (CD₃OD): δ 7.32 (d, J=8.50 Hz, 1H), 6.76 (dd, J=8.50, 2.50 Hz,1H), 6.71 (d, J=2.50 Hz, 1H), 4.18-4.48 (m, 4H), 4.16 (s, 2H), 3.94 (t,J=6.50 Hz, 2H), 3.67-3.79 (m, 1H), 2.70-2.77 (m, 2H), 2.20-2.29 (m, 5H),1.61-1.82 (m, 7H), 1.11-1.39 (m, 6H), 0.83-1.00 (m, 2H);

Melting point: 160-163° C.

Example 31-471-({1-methyl-6-[3-(4-methylphenyl)propoxy]-3,4-dihydro-2-naphthalenyl}methyl)-3-azetidinecarboxylicacid hydrochloride

TLC: Rf 0.31 (chloroform:methanol:aqueous ammonia=80:20:4);

¹H-NMR (CD₃OD): δ 7.32 (d, J=8.50 Hz, 1H), 7.06-7.08 (m, 4H), 6.75 (dd,J=8.50, 2.50 Hz, 1H), 6.71 (d, J=2.50 Hz, 1H), 4.17-4.48 (m, 4H), 4.16(s, 2H), 3.94 (t, J=6.00 Hz, 2H), 3.65-3.78 (m, 1H), 2.69-2.77 (m, 4H),2.19-2.29 (m, 8H), 1.97-2.09 (m, 2H).

Example 31-481-[(1-methyl-6-{3-[4-(trifluoromethyl)phenyl]propoxy}-3,4-dihydro-2-naphthalenyl)methyl]-3-azetidinecarboxylicacid hydrochloride

TLC: Rf 0.30 (chloroform:methanol:aqueous ammonia=80:20:4);

¹H-NMR (CD₃OD): δ 7.56 (d, J=8.00 Hz, 2H), 7.40 (d, J=8.00 Hz, 2H), 7.33(d, J=8.50 Hz, 1H), 6.76 (dd, J=8.50, 2.50 Hz, 1H), 6.71 (d, J=2.50 Hz,1H), 4.17-4.49 (m, 4H), 4.16 (s, 2H), 3.98 (t, J=6.00 Hz, 2H), 3.64-3.78(m, 1H), 2.89 (t, J=7.50 Hz, 2H), 2.69-2.77 (m, 2H), 2.20-2.29 (m, 5H),2.05-2.15 (m, 2H).

Example 31-491-({6-[3-(2-chlorophenyl)propoxy]-1-methyl-3,4-dihydro-2-naphthalenyl}methyl)-3-azetidinecarboxylicacid hydrochloride

TLC: Rf 0.30 (chloroform:methanol:aqueous ammonia=80:20:4);

¹H-NMR (CD₃OD): δ 7.25-7.38 (m, 3H), 7.13-7.24 (m, 2H), 6.77 (dd,J=8.50, 2.50 Hz, 1H), 6.73 (d, J=2.50 Hz, 1H), 4.18-4.43 (m, 4H), 4.16(s, 2H), 3.99 (t, J=6.00 Hz, 2H), 3.65-3.76 (m, 1H), 2.90-2.97 (m, 2H),2.70-2.77 (m, 2H), 2.20-2.29 (m, 5H), 2.02-2.13 (m, 2H).

Example 31-501-({6-[3-(2-fluorophenyl)propoxy]-1-methyl-3,4-dihydro-2-naphthalenyl}methyl)-3-azetidinecarboxylicacid hydrochloride

TLC: Rf 0.30 (chloroform:methanol:aqueous ammonia=80:20:4);

¹H-NMR (CD₃OD): δ 7.33 (d, J=8.50 Hz, 1H), 7.16-7.27 (m, 2H), 6.98-7.10(m, 2H), 6.76 (dd, J=8.50, 2.50 Hz, 1H), 6.72 (d, J=2.50 Hz, 1H),4.19-4.46 (m, 4H), 4.16 (s, 2H), 3.98 (t, J=6.00 Hz, 2H), 3.65-3.78 (m,1H), 2.83 (t, J=7.50 Hz, 2H), 2.70-2.77 (m, 2H), 2.20-2.29 (m, 5H),2.00-2.11 (m, 2H);

Melting point: 133-135° C.

Example 31-511-{[1-chloro-6-(4-phenylbutoxy)-3,4-dihydro-2-naphthalenyl]methyl}-3-azetidinecarboxylicacid hydrochloride

TLC: Rf 0.15 (n-butanol:acetic acid:water=20:4:1);

¹H-NMR (CD₃OD): δ 7.56 (d, J=8.60 Hz, 1H), 7.06-7.35 (m, 5H), 6.63-6.88(m, 2H), 4.29 (s, 2H), 4.22-4.59 (m, 4H), 3.94-4.06 (m, 2H), 3.61-3.81(m, 1H), 2.84 (t, J=8.40 Hz, 2H), 2.60-2.75 (m, 2H), 2.47 (t, J=7.20 Hz,2H), 1.67-1.90 (m, 4H).

Example 31-523-({[1-chloro-6-(4-phenylbutoxy)-3,4-dihydro-2-naphthalenyl]methyl}amino)propanoicacid hydrochloride

TLC: Rf 0.27 (n-butanol:acetic acid:water=20:4:1);

¹H-NMR (CD₃OD): δ 7.55 (d, J=8.4 Hz, 1H), 7.00-7.35 (m, 5H), 6.64-6.86(m, 2H), 4.08 (s, 2H), 3.94-4.04 (m, 2H), 3.19-3.45 (m, 2H), 2.88 (t,J=7.5 Hz, 2H), 2.79 (t, J=6.5 Hz, 2H), 2.63-2.72 (m, 2H), 2.53 (t, J=7.5Hz, 2H), 1.74-1.84 (m, 4H).

Example 31-531-({6-[3-(4-fluorophenyl)propoxy]-1-methyl-3,4-dihydro-2-naphthalenyl}methyl)-3-azetidinecarboxylicacid hydrochloride

TLC: Rf 0.26 (chloroform:methanol:aqueous ammonia=80:20:4);

¹H-NMR (CD₃OD): δ 7.32 (d, J=8.50 Hz, 1H), 7.20 (dd, J=8.50, 5.50 Hz,2H), 6.98 (t, J=8.50 Hz, 2H), 6.76 (dd, J=8.50, 2.50 Hz, 1H), 6.72 (d,J=2.50 Hz, 1H), 4.18-4.43 (m, 4H), 4.16 (s, 2H), 3.95 (t, J=6.00 Hz,2H), 3.66-3.75 (m, 1H), 2.69-2.82 (m, 4H), 2.20-2.28 (m, 5H), 1.99-2.10(m, 2H);

Melting point: 135-137° C.

Example 31-541-({6-[2-(4-tert-butylphenyl)ethoxy]-1-methyl-3,4-dihydro-2-naphthalenyl}methyl)-3-azetidinecarboxylicacid hydrochloride

TLC: Rf 0.27 (chloroform:methanol:aqueous ammonia=80:20:4);

¹H-NMR (CD₃OD): δ 7.30-7.35 (m, 3H), 7.20 (d, J=8.50 Hz, 2H), 6.77 (dd,J=8.50, 2.50 Hz, 1H), 6.72 (d, J=2.50 Hz, 1H), 4.20-4.46 (m, 4H),4.13-4.19 (m, 4H), 3.61-3.78 (m, 1H), 3.01 (t, J=7.00 Hz, 2H), 2.69-2.76(m, 2H), 2.18-2.28 (m, 5H), 1.30 (s, 9H).

Example 31-551-{[6-(1,1′-biphenyl-4-ylmethoxy)-1-methyl-3,4-dihydro-2-naphthalenyl]methyl}-3-azetidinecarboxylicacid hydrochloride

TLC: Rf 0.28 (chloroform:methanol:aqueous ammonia=80:20:4);

¹H-NMR (CD₃OD): δ 7:58-7.64 (m, 4H), 7.49 (d, J=8.00 Hz, 2H), 7.42 (t,J=8.00 Hz, 2H), 7.29-7.36 (m, 2H), 6.87 (dd, J=8.50, 2.50 Hz, 1H), 6.83(d, J=2.50 Hz, 1H), 5.14 (s, 2H), 4.21-4.44 (m, 4H), 4.15 (s, 2H),3.64-3.77 (m, 1H), 2.70-2.79 (m, 2H), 2.19-2.30 (m, 5H).

Example 31-561-({6-[3-(2,6-dichlorophenyl)propoxy]-1-methyl-3,4-dihydro-2-naphthalenyl}methyl)-3-azetidinecarboxylicacid hydrochloride

TLC: Rf 0.17 (n-butanol:acetic acid:water=20:4:1);

¹H-NMR (CD₃OD): δ 7.30-7.37 (m, 3H), 7.14-7.20 (m, 1H), 6.77 (dd, J=8.7,2.6 Hz, 1H), 6.72 (d, J=2.6 Hz, 1H), 4.19-4.45 (m, 4H), 4.16 (s, 2H),4.06 (t, J=6.1 Hz, 2H), 3.62-3.78 (m, 1H), 3.07-3.18 (m, 2H), 2.68-2.78(m, 2H), 2.22 (s, 3H), 2.19-2.29 (m, 2H), 1.97-2.10 (m, 2H).

Example 31-571-[(6-{3-[3,5-bis(trifluoromethyl)phenyl]propoxy}-1-methyl-3,4-dihydro-2-naphthalenyl)methyl]-3-azetidinecarboxylicacid hydrochloride

TLC: Rf 0.20 (n-butanol:acetic acid:water=20:4:1);

¹H-NMR (CD₃OD): δ 7.82 (s, 2H), 7.77 (s, 1H), 7.33 (d, J=8.6 Hz, 1H),6.75 (dd, J=8.6, 2.6 Hz, 1H), 6.70 (d, J=2.6 Hz, 1H), 4.19-4.45 (m, 4H),4.16 (s, 2H), 4.00 (t, J=6.0 Hz, 2H), 3.62-3.77 (m, 1H), 2.95-3.04 (m,2H), 2.67-2.76 (m, 2H), 2.22 (s, 3H), 2.19-2.30 (m, 2H), 2.07-2.18 (m,2H).

Example 31-581-{[1-methyl-6-(octyloxy)-3,4-dihydro-2-naphthalenyl]methyl}-β-azetidinecarboxylicacid hydrochloride

TLC: Rf 0.17 (n-butanol:acetic acid:water=20:4:1);

¹H-NMR (CD₃OD): δ 7.32 (d, J=8.6 Hz, 1H), 6.76 (dd, J=8.6, 2.6 Hz, 1H),6.72 (d, J=2.6 Hz, 1H), 4.18-4.44 (m, 4H), 4.16 (s, 2H), 3.96 (t, J=6.4Hz, 2H), 3.63-3.77 (m, 1H), 2.69-2.77 (m, 2H), 2.22 (s, 3H), 2.17-2.31(m, 2H), 1.68-1.81 (m, 2H), 1.23-1.53 (m, 10H), 0.84-0.95 (m, 3H).

Example 31-591-{[6-(3,3-diphenylpropoxy)-1-methyl-3,4-dihydro-2-naphthalenyl]methyl}-3-azetidinecarboxylicacid hydrochloride

TLC: Rf 0.27 (n-butanol:acetic acid:water=20:4:1);

¹H-NMR (CD₃OD): δ 7.10-7.37 (m, 11H), 6.63-6.73 (m, 2H), 4.19-4.45 (m,5H), 4.15 (s, 2H), 3.88 (t, J=6.3 Hz, 2H), 3.64-3.77 (m, 1H), 2.66-2.76(m, 2H), 2.44-2.57 (m, 2H), 2.20 (s, 3H), 2.16-2.29 (m, 2H);

Melting point: 77-83° C.

Example 31-601-({1-methyl-6-[(4-propylbenzyl)oxy]-3,4-dihydro-2-naphthalenyl}methyl)-3-azetidinecarboxylicacid hydrochloride

TLC: Rf 0.23 (n-butanol:acetic acid:water=20:4:1);

¹H-NMR (CD₃OD): δ 7.27-7.36 (m, 3H), 7.18 (d, J=8.1 Hz, 2H), 6.84 (dd,J=8.1, 2.7 Hz, 1H), 6.80 (d, J=2.7 Hz, 1H), 5.04 (s, 2H), 4.21-4.43 (m,4H), 4.15 (s, 2H), 3.62-3.76 (m, 1H), 2.68-2.78 (m, 2H), 2.58 (t, J=7.8Hz, 2H), 2.22 (s, 3H), 2.19-2.30 (m, 2H), 1.56-1.71 (m, 2H), 0.93 (t,J=7.3 Hz, 3H);

Melting point: 144-150° C.

Example 31-611-({6-[(4-isobutylbenzyl)oxy]-1-methyl-3,4-dihydro-2-naphthalenyl}methyl)-3-azetidinecarboxylicacid hydrochloride

TLC: Rf 0.20 (n-butanol:acetic acid:water=20:4:1);

¹H-NMR (CD₃OD): δ 7.24-7.43 (m, 3H), 7.15 (d, J=8.1 Hz, 2H), 6.73-6.94(m, 2H), 5.04 (s, 2H), 4.16 (s, 2H), 4.06-4.47 (m, 4H), 3.60-3.82 (m,1H), 2.73 (t, J=8.4 Hz, 2H), 2.48 (d, J=7.1 Hz, 2H), 2.13-2.31 (m, 5H),1.69-1.98 (m, 1H), 0.90 (d, J=6.6 Hz, 6H).

Example 31-621-({6-[(4-tert-butylbenzyl)oxy]-1-methyl-3,4-dihydro-2-naphthalenyl}methyl)-3-azetidinecarboxylicacid hydrochloride

TLC: Rf 0.20 (n-butanol:acetic acid:water=20:4:1);

¹H-NMR (CD₃OD): δ 7.37-7.43 (m, 2H), 7.29-7.36 (m, 3H), 6.84 (dd, J=8.4,2.7 Hz, 1H), 6.80 (d, J=2.7 Hz, 1H), 5.04 (s, 2H), 4.19-4.43 (m, 4H),4.16 (s, 2H), 3.62-3.78 (m, 1H), 2.69-2.77 (m, 2H), 2.21 (s, 3H),2.19-2.29 (m, 2H), 1.31 (s, 9H).

Example 31-631-({1-methyl-6-[3-(2-methylphenyl)propoxy]-3,4-dihydro-2-naphthalenyl}methyl)-3-azetidinecarboxylicacid hydrochloride

TLC: Rf 0.22 (n-butanol:acetic acid:water=20:4:1);

¹H-NMR (CD₃OD): δ 7.33 (d, J=8.6 Hz, 1H), 7.02-7.15 (m, 4H), 6.77 (dd,J=8.6, 2.6 Hz, 1H), 6.73 (d, J=2.6 Hz, 1H), 4.21-4.42 (m, 4H), 4.16 (s,2H), 3.98 (t, J=6.0 Hz, 2H), 3.63-3.77 (m, 1H), 2.68-2.84 (m, 4H), 2.30(s, 3H), 2.22 (s, 3H), 2.19-2.32 (m, 2H), 1.96-2.07 (m, 2H);

Melting point: 160-165° C.

Example 31-641-({1-methyl-6-[(4-phenylbutyl)sulfanyl]-3,4-dihydro-2-naphthalenyl}methyl)-3-azetidinecarboxylicacid hydrochloride

TLC: Rf 0.17 (chloroform:methanol:aqueous ammonia=20:5:1);

¹H-NMR (CD₃OD): δ 7.31 (d, J=8.2 Hz, 1H), 7.05-7.27 (m, 7H), 4.23-4.42(m, 4H), 4.18 (s, 2H), 3.62-3.77 (m, 1H), 2.95 (t, J=7.0 Hz, 2H),2.67-2.78 (m, 2H), 2.61 (t, J=7.4 Hz, 2H), 2.22 (s, 3H), 2.20-2.30 (m,2H), 1.57-1.81 (m, 4H).

Example 31-651-{[1-methyl-6-(2-naphthylmethoxy)-3,4-dihydro-2-naphthalenyl]methyl}-3-azetidinecarboxylicacid hydrochloride

TLC: Rf 0.32 (chloroform:methanol:aqueous ammonia=80:20:4);

¹H-NMR (CD₃OD): δ 7.81-7.91 (m, 4H), 7.54 (dd, J=8.50, 1.50 Hz, 1H),7.44-7.51 (m, 2H), 7.35 (d, J=8.50 Hz, 1H), 6.91 (dd, J=8.50, 2.50 Hz,1H), 6.87 (d, J=2.50 Hz, 1H), 5.26 (s, 2H), 4.19-4.45 (m, 4H), 4.16 (s,2H), 3.64-3.77 (m, 1H), 2.74 (t, J=8.00 Hz, 2H), 2.20-2.29 (m, 5H).

Example 31-661-{[1-methyl-6-(2-quinolinylmethoxy)-3,4-dihydro-2-naphthalenyl]methyl}-3-azetidinecarboxylicacid dihydrochloride

TLC: Rf 0.29 (chloroform:methanol:aqueous ammonia=80:20:4);

¹H-NMR (CD₃OD): δ 9.17 (d, J=8.50 Hz, 1H), 8.32-8.41 (m, 2H), 8.15-8.24(m, 2H), 7.95-8.03 (m, 1H), 7.44 (d, J=9.00 Hz, 1H), 7.03-7.07 (m, 2H),5.73 (s, 2H), 4.38-4.49 (m, 2H), 4.16-4.34 (m, 4H), 3.65-3.82 (m, 1H),2.80 (t, J=8.00 Hz, 2H), 2.23-2.34 (m, 5H).

Example 31-671-{[6-(1-benzothien-2-ylmethoxy)-1-methyl-3,4-dihydro-2-naphthalenyl]methyl}-3-azetidinecarboxylicacid hydrochloride

TLC: Rf 0.31 (chloroform:methanol:aqueous ammonia=80:20:4);

¹H-NMR (CD₃OD): δ 7.80-7.84 (m, 1H), 7.73-7.79 (m, 1H), 7.27-7.39 (m,4H), 6.91 (dd, J=8.50, 2.50 Hz, 1H), 6.86 (d, J=2.50 Hz, 1H), 5.38 (d,J=1.00 Hz, 2H), 4.18-4.43 (m, 4H), 4.16 (s, 2H), 3.63-3.77 (m, 1H), 2.75(t, J=8.00 Hz, 2H), 2.20-2.29 (m, 5H).

Example 31-681-({6-[3-(3,4-difluorophenyl)propoxy]-1-methyl-3,4-dihydro-2-naphthalenyl}methyl)-3-azetidinecarboxylicacid hydrochloride

TLC: Rf 0.32 (chloroform:methanol:aqueous ammonia=80:20:4);

¹H-NMR (CD₃OD): δ 7.33 (d, J=8.50 Hz, 1H), 7.07-7.18 (m, 2H), 6.96-7.03(m, 1H), 6.76 (dd, J=8.50, 2.50 Hz, 1H), 6.72 (d, J=2.50 Hz, 1H),4.18-4.47 (m, 4H), 4.16 (s, 2H), 3.96 (t, J=6.00 Hz, 2H), 3.66-3.78 (m,1H), 2.68-2.82 (m, 4H), 2.20-2.30 (m, 5H), 2.00-2.10 (m, 2H);

Melting point: 132-133° C.

Example 31-691-{[6-(4-butylphenoxy)-1-methyl-3,4-dihydronaphthalen-2-yl]methyl}azetidine-3-carboxylicacid hydrochloride

TLC: Rf 0.14 (n-butanol:acetic acid:water=20:4:1);

¹H-NMR (CD₃OD): δ 7.38 (d, J=8.6 Hz, 1H), 7.17 (d, J=8.6 Hz, 2H),6.85-6.98 (m, 2H), 6.73-6.83 (m, 2H), 4.20-4.45 (m, 4H), 4.17 (s, 2H),3.58-3.81 (m, 1H), 2.67-2.79 (m, 2H), 2.60 (t, J=7.8 Hz, 2H), 2.23 (s,3H), 2.17-2.32 (m, 2H), 1.52-1.66 (m, 2H), 1.29-1.44 (m, 2H), 0.94 (t,J=7.3 Hz, 3H).

Example 31-701-{[6-(1-benzofuran-2-ylmethoxy)-1-methyl-3,4-dihydro-2-naphthalenyl]methyl}-3-azetidinecarboxylicacid hydrochloride

TLC: Rf 0.28 (chloroform:methanol:aqueous ammonia=80:20:4);

¹H-NMR (CD₃OD): δ 7.55-7.59 (m, 1H), 7.44-7.49 (m, 1H), 7.36 (d, J=8.50Hz, 1H), 7.25-7.32 (m, 1H), 7.18-7.24 (m, 1H), 6.92 (dd, J=8.50, 2.50Hz, 1H), 6.85-6.88 (m, 2H), 5.20 (s, 2H), 4.20-4.45 (m, 4H), 4.16 (s,2H), 3.66-3.78 (m, 1H), 2.75 (t, J=7.50 Hz, 2H), 2.19-2.29 (m, 5H).

Example 31-711-({1-methyl-6-[(3-phenyl-1,2,4-oxadiazol-5-yl)methoxy]-3,4-dihydro-2-naphthalenyl}methyl)-3-azetidinecarboxylicacid hydrochloride

TLC: Rf 0.27 (chloroform:methanol:aqueous ammonia=80:20:4);

¹H-NMR (CD₃OD): δ 8.03-8.09 (m, 2H), 7.47-7.57 (m, 3H), 7.39 (d, J=8.50Hz, 1H), 6.90-6.97 (m, 2H), 5.46 (s, 2H), 4.20-4.43 (m, 4H), 4.16 (s,2H), 3.63-3.76 (m, 1H), 2.77 (t, J=7.50 Hz, 2H), 2.20-2.31 (m, 5H).

Example 31-721-[(1-methyl-6-{[(2E)-3-phenyl-2-propenyl]oxy}-3,4-dihydro-2-naphthalenyl)methyl]-3-azetidinecarboxylicacid hydrochloride

TLC: Rf 0.28 (chloroform:methanol:aqueous ammonia=80:20:4);

¹H-NMR (CD₃OD): δ 7.37-7.45 (m, 2H), 7.27-7.38 (m, 3H), 7.19-7.26 (m,1H), 6.85 (dd, J=8.50, 2.50 Hz, 1H), 6.81 (d, J=2.50 Hz, 1H), 6.74 (dt,J=16.00, 1.50 Hz, 1H), 6.44 (dt, J=16.00, 5.50 Hz, 1H), 4.71 (dd,J=5.50, 1.50 Hz, 2H), 4.19-4.44 (m, 4H), 4.16 (s, 2H), 3.65-3.76 (m,1H), 2.72-2.79 (m, 2H), 2.20-2.30 (m, 5H).

Example 31-731-({6-[3-(3-fluorophenyl)propoxy]-1-methyl-3,4-dihydro-2-naphthalenyl}methyl)-3-azetidinecarboxylicacid hydrochloride

TLC: Rf 0.28 (chloroform:methanol:aqueous ammonia=80:20:4);

¹H-NMR (CD₃OD): δ 7.33 (d, J=8.50 Hz, 1H), 7.21-7.30 (m, 1H), 7.02 (d,J=8.00 Hz, 1H), 6.84-6.98 (m, 2H), 6.76 (dd, J=8.50, 2.50 Hz, 1H), 6.72(d, J=2.50 Hz, 1H), 4.20-4.43 (m, 4H), 4.16 (s, 2H), 3.96 (t, J=6.00 Hz,2H), 3.64-3.78 (m, 1H), 2.81 (t, J=7.50 Hz, 2H), 2.73 (t, J=8.00 Hz,2H), 2.19-2.29 (m, 5H), 2.01-2.12 (m, 2H);

Melting point: 157-161° C.

Example 31-741-({6-[3-(2,4-dichlorophenyl)propoxy]-1-methyl-3,4-dihydronaphthalen-2-yl}methyl)azetidine-3-carboxylicacid hydrochloride

TLC: Rf 0.14 (n-butanol:acetic acid:water=20:4:1);

¹H-NMR (CD₃OD): δ 7.41 (d, J=2.2 Hz, 1H), 7.33 (d, J=8.6 Hz, 1H), 7.28(d, J=8.4 Hz, 1H), 7.22 (dd, J=8.4, 2.2 Hz, 1H), 6.76 (dd, J=8.6, 2.4Hz, 1H), 6.71 (d, J=2.4 Hz, 1H), 4.19-4.42 (m, 4H), 4.16 (s, 2H), 3.99(t, J=6.0 Hz, 2H), 3.62-3.76 (m, 1H), 2.87-2.96 (m, 2H), 2.69-2.78 (m,2H), 2.22 (s, 3H), 2.18-2.29 (m, 2H), 2.00-2.12 (m, 2H);

Melting point: 121-126° C.

Example 31-751-({6-[3-(2,4-dimethylphenyl)propoxy]-1-methyl-3,4-dihydronaphthalen-2-yl}methyl)azetidine-3-carboxylicacid hydrochloride

TLC: Rf 0.16 (n-butanol:acetic acid:water=20:4:1);

¹H-NMR (CD₃OD): δ 7:32 (d, J=8.6 Hz, 1H), 6.99 (d, J=7.5 Hz, 1H), 6.93(s, 1H), 6.88 (d, J=7.5 Hz, 1H), 6.76 (dd, J=8.6, 2.6 Hz, 1H), 6.72 (d,J=2.6 Hz, 1H), 4.19-4.43 (m, 4H), 4.16 (s, 2H), 3.96 (t, J=6.1 Hz, 2H),3.62-3.77 (m, 1H), 2.67-2.80 (m, 4H), 2.25 (s, 3H), 2.24 (s, 3H), 2.22(s, 3H), 2.15-2.32 (m, 2H), 1.91-2.04 (m, 2H);

Melting point: 132-136° C.

Example 31-761-({6-[(4-ethylbenzyl)oxy]-1-methyl-3,4-dihydronaphthalen-2-yl}methyl)azetidine-3-carboxylicacid hydrochloride

TLC: Rf 0.16 (n-butanol:acetic acid:water=20:4:1);

¹H-NMR (CD₃OD): δ 7.29-7.37 (m, 3H), 7.20 (d, J=8.1 Hz, 2H), 6.84 (dd,J=8.5, 2.8 Hz, 1H), 6.80 (d, J=2.8 Hz, 1H), 5.04 (s, 2H), 4.22-4.42 (m,4H), 4.15 (s, 2H), 3.63-3.78 (m, 1H), 2.70-2.79 (m, 2H), 2.64 (q, J=7.6Hz, 2H), 2.21 (s, 3H), 2.19-2.30 (m, 2H), 1.22 (t, J=7.6 Hz, 3H).

Example 31-771-({6-[(4-cyclohexylbenzyl)oxy]-1-methyl-3,4-dihydronaphthalen-2-yl}methyl)azetidine-3-carboxylicacid hydrochloride

TLC: Rf 0.14 (n-butanol:acetic acid:water=20:4:1);

¹H-NMR (CD₃OD): δ 7.27-7.41 (m, 3H), 7.20 (d, J=7.8 Hz, 2H), 6.84 (dd,J=8.4, 2.6 Hz, 1H), 6.80 (d, J=2.6 Hz, 1H), 5.03 (s, 2H), 4.20-4.43 (m,4H), 4.15 (s, 2H), 3.62-3.77 (m, 1H), 2.66-2.78 (m, 2H), 2.45-2.57 (m,1H), 2.21 (s, 3H), 2.17-2.29 (m, 2H), 1.70-1.90 (m, 5H), 1.34-1.54 (m,5H);

Melting point: 154-158° C.

Example 31-781-({6-[3-(4-chlorophenyl)propoxy]-1-ethyl-3,4-dihydronaphthalen-2-yl}methyl)azetidine-3-carboxylicacid hydrochloride

TLC: Rf 0.27 (chloroform:methanol:aqueous ammonia=80:5:1);

¹H-NMR (CD₃OD): δ 7.34 (d, J=8.60 Hz, 1H), 7.23-7.28 (m, 2H), 7.17-7.22(m, 2H), 6.77 (dd, J=8.60, 2.56 Hz, 1H), 6.72 (d, J=2.56 Hz, 1H), 4.15(s, 2H), 4.09-4.54 (m, 4H), 3.96 (t, J=6.13 Hz, 2H), 3.63-3.78 (m, 1H),2.64-2.85 (m, 6H), 2.20 (t, J=7.80 Hz, 2H), 1.96-2.13 (m, 2H), 1.11 (t,J=7.50 Hz, 3H);

Melting point: 102-105° C.

Example 31-791-{[3-methyl-6-(4-phenylbutoxy)-1-benzofuran-2-yl]methyl}azetidine-3-carboxylicacid

TLC: Rf 0.30 (chloroform:methanol:aqueous ammonia=80:20:4);

¹H-NMR (DMSO-D₆): δ 7.36 (d, J=8.60 Hz, 1H), 7.13-7.32 (m, 5H), 7.06 (d,J=2.20 Hz, 1H), 6.82 (dd, J=8.60, 2.20 Hz, 1H), 3.97-4.03 (m, 2H), 3.60(s, 2H), 3.36-3.44 (m, 2H), 3.25 (t, J=6.68 Hz, 2H), 3.08-3.20 (m, 1H),2.60-2.70 (m, 2H), 2.15 (s, 3H), 1.68-1.79 (m, 4H).

Example 31-801-({6-[3-(2,4-difluorophenyl)propoxy]-1-methyl-3,4-dihydro-2-naphthalenyl}methyl)-3-azetidinecarboxylicacid hydrochloride

TLC: Rf 0.20 (chloroform:methanol:aqueous ammonia=80:20:4);

¹H-NMR (CD₃OD): δ 7.33 (d, J=8.50 Hz, 1H), 7.21-7.30 (m, 1H), 6.82-6.92(m, 2H), 6.76 (dd, J=8.50, 2.50 Hz, 1H), 6.72 (d, J=2.50 Hz, 1H),4.18-4.44 (m, 4H), 4.16 (s, 2H), 3.97 (t, J=6.00 Hz, 2H), 3.66-3.77 (m,1H), 2.81 (t, J=7.50 Hz, 2H), 2.69-2.77 (m, 2H), 2.20-2.29 (m, 5H),1.99-2.10 (m, 2H);

Melting point: 126-129° C.

Example 31-811-({6-[2-(2,3-dihydro-1H-inden-2-yl)ethoxy]-1-methyl-3,4-dihydro-2-naphthalenyl}methyl)-3-azetidinecarboxylicacid hydrochloride

TLC: Rf 0.20 (chloroform:methanol:aqueous ammonia=80:20:4);

¹H-NMR (CD₃OD): δ 7.34 (d, J=8.50 Hz, 1H), 7.12-7.17 (m, 2H), 7.03-7.10(m, 2H), 6.80 (dd, J=8.50, 2.50 Hz, 1H), 6.75 (d, J=2.50 Hz, 1H),4.19-4.43 (m, 4H), 4.16 (s, 2H), 4.08 (t, J=6.50 Hz, 2H), 3.64-3.77 (m,1H), 2.99-3.14 (m, 2H), 2.60-2.79 (m, 5H), 2.20-2.30 (m, 5H), 1.92-2.02(m, 2H);

Melting point: 129-132° C.

Example 31-821-{[6-(2,3-dihydro-1H-inden-2-ylmethoxy)-1-methyl-3,4-dihydro-2-naphthalenyl]methyl}-3-azetidinecarboxylicacid hydrochloride

TLC: Rf 0.20 (chloroform:methanol:aqueous ammonia=80:20:4);

¹H-NMR (CD₃OD): δ 7.33 (d, J=8.50 Hz, 1H), 7.15-7.21 (m, 2H), 7.07-7.13(m, 2H), 6.79 (dd, J=8.50, 2.50 Hz, 1H), 6.74 (d, J=2.50 Hz, 1H),4.21-4.41 (m, 4H), 4.15 (s, 2H), 3.97 (d, J=7.00 Hz, 2H), 3.63-3.76 (m,1H), 3.06-3.18 (m, 2H), 2.78-2.99 (m, 3H), 2.69-2.77 (m, 2H), 2.19-2.29(m, 5H).

Example 31-831-{[6-(bicyclo[4.2.0]octa-1,3,5-trien-7-ylmethoxy)-1-methyl-3,4-dihydro-2-naphthalenyl]methyl}-3-azetidinecarboxylicacid hydrochloride

TLC: Rf 0.20 (chloroform:methanol:aqueous ammonia=80:20:4);

¹H-NMR (CD₃OD): δ 7.33 (d, J=8.50 Hz, 1H), 7.05-7.24 (m, 4H), 6.81 (dd,J=8.50, 2.50 Hz, 1H), 6.77 (d, J=2.50 Hz, 1H), 4.24-4.43 (m, 4H), 4.20(d, J=7.00 Hz, 2H), 4.16 (s, 2H), 3.85-3.95 (m, 1H), 3.64-3.77 (m, 1H),3.38 (dd, J=14.00, 5.00 Hz, 1H), 2.96 (dd, J=14.00, 2.50 Hz, 1H),2.70-2.78 (m, 2H), 2.20-2.29 (m, 5H).

Example 31-841-[(1-methyl-6-{3-[3-(trifluoromethyl)phenyl]propoxy}-3,4-dihydronaphthalen-2-yl)methyl]azetidine-3-carboxylicacid

TLC: Rf 0.26 (chloroform:methanol:aqueous ammonia=20:5:1);

¹H-NMR (CD₃OD): δ 7.42-7.54 (m, 4H), 7.31 (d, J=8.60 Hz, 1H), 6.76 (dd,J=8.60, 2.75 Hz, 1H), 6.71 (d, J=2.75 Hz, 1H), 4.11-4.27 (m, 4H), 4.08(s, 2H), 3.97 (t, J=6.13 Hz, 2H), 3.33-3.51 (m, 1H), 2.89 (t, J=7.87 Hz,2H), 2.72 (t, J=8.05 Hz, 2H), 2.18-2.29 (m, 2H), 2.20 (s, 3H), 2.00-2.16(m, 2H);

Melting point: 125-133° C.

Example 31-851-({1-methyl-6-[3-(3-methylphenyl)propoxy]-3,4-dihydronaphthalen-2-yl}methyl)azetidine-3-carboxylicacid

TLC: Rf 0.26 (chloroform:methanol:aqueous ammonia=20:5:1);

¹H-NMR (CD₃OD): δ 7.30 (d, J=8.60 Hz, 1H), 7.06-7.19 (m, 1H), 6.92-7.04(m, 3H), 6.74 (dd, J=8.60, 2.74 Hz, 1H), 6.70 (d, J=2.74 Hz, 1H),4.07-4.24 (m, 4H), 4.05 (s, 2H), 3.94 (t, J=6.22 Hz, 2H), 3.33-3.49 (m,1H), 2.64-2.81 (m, 4H), 2.28 (s, 3H), 2.19 (s, 3H), 2.16-2.29 (m, 2H),1.95-2.10 (m, 2H);

Melting point: 148-153° C.

Example 31-861-({6-[3-(3-chlorophenyl)propoxy]-1-methyl-3,4-dihydronaphthalen-2-yl}methyl)azetidine-3-carboxylicacid

TLC: Rf 0.26 (chloroform:methanol:aqueous ammonia=20:5:1);

¹H-NMR (CD₃OD): δ 7.31 (d, J=8.60 Hz, 1H), 7.20-7.28 (m, 2H), 7.08-7.20(m, 2H), 6.75 (dd, J=8.60, 2.74 Hz, 1H), 6.71 (d, J=2.74 Hz, 1H),4.10-4.26 (m, 4H), 4.07 (s, 2H), 3.96 (t, J=6.13 Hz, 2H), 3.34″-3.51 (m,1H), 2.79 (t, J=7.87 Hz, 2H), 2.66-2.75 (m, 2H), 2.20 (s, 3H), 2.16-2.28(m, 2H), 1.98-2.11 (m, 2H);

Melting point: 151-153° C.

Example 31-871-({6-[3-(3,4-dichlorophenyl)propoxy]-1-methyl-3,4-dihydronaphthalen-2-yl}methyl)azetidine-3-carboxylicacid

TLC: Rf 0.26 (chloroform:methanol:aqueous ammonia=20:5:1);

¹H-NMR (CD₃OD): δ 7.39 (d, J=8.23 Hz, 1H), 7.36-7.39 (m, 1H), 7.30 (d,J=8.42 Hz, 1H), 7.14 (dd, J=8.23, 2.20 Hz, 1H), 6.75 (dd, J=8.42, 2.65Hz, 1H), 6.70 (d, J=2.65 Hz, 1H), 4.06-4.25 (m, 4H), 4.04 (s, 2H), 3.96(t, J=6.13 Hz, 2H), 3.33-3.47 (m, 1H), 2.79 (t, J=8.05 Hz, 2H),2.67-2.75 (m, 2H), 2.19 (s, 3H), 2.16-2.28 (m, 2H), 1.99-2.12 (m, 2H);

Melting point: 74-81° C.

Example 31-881-({6-[2-(4-ethylphenyl)ethoxy]-1-methyl-3,4-dihydronaphthalen-2-yl}methyl)azetidine-3-carboxylicacid

TLC: Rf 0.28 (chloroform:methanol:aqueous ammonia=20:5:1);

¹H-NMR (CD₃OD): δ 7.30 (d, J=8.42 Hz, 1H), 7.19 (d, J=7.80 Hz, 2H), 7.12(d, J=7.80 Hz, 2H), 6.76 (dd, J=8.42, 2.56 Hz, 1H), 6.71 (d, J=2.56 Hz,1H), 4.07-4.27 (m, 6H), 4.08 (s, 2H), 3.34-3.48 (m, 1H), 3.01 (t, J=6.86Hz, 2H), 2.66-2.76 (m, 2H), 2.60 (q, J=7.75 Hz, 2H), 2.18-2.27 (m, 2H),2.19 (s, 3H), 1.20 (t, J=7.68 Hz, 3H);

Melting point: 158-163° C.

Example 31-891-({6-[2-(4-isopropylphenyl)ethoxy]-1-methyl-3,4-dihydronaphthalen-2-yl}methyl)azetidine-3-carboxylicacid

TLC: Rf 0.30 (chloroform:methanol:aqueous ammonia=20:5:1);

¹H-NMR (CD₃OD): δ 7.30 (d, J=8.42 Hz, 1H), 7.20 (d, J=8.24 Hz, 2H), 7.15(d, J=8.24 Hz, 2H), 6.76 (dd, J=8.42, 2.65 Hz, 1H), 6.71 (d, J=2.65 Hz,1H), 4.10-4.27 (m, 6H), 4.07 (s, 2H), 3.33-3.49 (m, 1H), 3.01 (t, J=6.86Hz, 2H), 2.77-2.93 (m, 1H), 2.62-2.77 (m, 2H), 2.19 (s, 3H), 2.15-2.29(m, 2H), 1.22 (d, J=6.95 Hz, 6H);

Melting point: 148-152° C.

Example 31-901-[(1-methyl-6-{3-[3-(trifluoromethoxy)phenyl]propoxy}-3,4-dihydronaphthalen-2-yl)methyl]azetidine-3-carboxylicacid

TLC: Rf 0.28 (chloroform:methanol:aqueous ammonia=20:5:1);

¹H-NMR (CD₃OD): δ 7.28-7.40 (m, 2H), 7.18-7.25 (m, 1H), 7.02-7.15 (m,2H), 6.76 (dd, J=8.60, 2.75 Hz, 1H), 6.71 (d, J=2.75 Hz, 1H), 4.12-4.28(m, 4H), 4.08 (s, 2H), 3.97 (t, J=6.13 Hz, 2H), 3.35-3.52 (m, 1H), 2.84(t, J=7.86 Hz, 2H), 2.65-2.78 (m, 2H), 2.21 (s, 3H), 2.16-2.31 (m, 2H),1.97-2.14 (m, 2H);

Melting point: 136-139° C.

Example 31-911-{[1-methyl-6-(3-phenylbutoxy)-3,4-dihydro-2-naphthalenyl]methyl}-3-azetidinecarboxylicacid hydrochloride

TLC: Rf 0.30 (chloroform:methanol:aqueous ammonia=80:20:4);

¹H-NMR (CD₃OD): δ 7.10-7.34 (m, 6H), 6.68 (dd, J=8.50, 2.50 Hz, 1H),6.64 (d, J=2.50 Hz, 1H), 4.18-4.46 (m, 4H), 4.15 (s, 2H), 3.65-3.94 (m,3H), 2.91-3.04 (m, 1H), 2.67-2.75 (m, 2H), 2.18-2.28 (m, 5H), 1.93-2.12(m, 2H), 1.30 (d, J=7.00 Hz, 3H);

Melting point: 127-133° C.

Example 31-921-{[1-methyl-6-(2-methyl-3-phenylpropoxy)-3,4-dihydro-2-naphthalenyl]methyl}-3-azetidinecarboxylicacid hydrochloride

TLC: Rf 0.30 (chloroform:methanol:aqueous ammonia=80:20:4);

¹H-NMR (CD₃OD): δ 7.32 (d, J=8.50 Hz, 1H), 7.21-7.28 (m, 2H), 7.12-7.19(m, 3H), 6.75 (dd, J=8.50, 2.50 Hz, 1H), 6.70 (d, J=2.50 Hz, 1H),4.36-4.48 (m, 2H), 4.19-4.33 (m, 2H), 4.16 (s, 2H), 3.65-3.86 (m, 3H),2.84 (dd, J=13.00, 6.50 Hz, 1H), 2.73 (t, J=8.00 Hz, 2H), 2.55 (dd,J=13.00, 7.50 Hz, 1H), 2.15-2.29 (m, 6H), 1.01 (d, J=7.00 Hz, 3H);

Melting point: 105-110° C.

Example 31-931-{[1-methyl-6-(1-methyl-3-phenylpropoxy)-3,4-dihydro-2-naphthalenyl]methyl}-3-azetidinecarboxylicacid hydrochloride

TLC: Rf 0.30 (chloroform:methanol:aqueous ammonia=80:20:4);

¹H-NMR (CD₃OD): δ 7.31 (d, J=8.50 Hz, 1H), 7.20-7.27 (m, 2H), 7.10-7.18(m, 3H), 6.72 (dd, J=8.50, 2.50 Hz, 1H), 6.65 (d, J=2.50 Hz, 1H),4.20-4.47 (m, 5H), 4.16 (s, 2H), 3.64-3.80 (m, 1H), 2.66-2.79 (m, 4H),2.19-2.31 (m, 5H), 1.80-2.09 (m, 2H), 1.29 (d, J=6.00 Hz, 3H).

Example 31-941-({6-[1-(4-isobutylphenyl)ethoxy]-1-methyl-3,4-dihydronaphthalen-2-yl}methyl)azetidine-3-carboxylicacid hydrochloride

TLC: Rf 0.18 (n-butanol:acetic acid:water=20:4:1);

¹H-NMR (CD₃OD): δ 7.19-7.29 (m, 3H), 7.09 (d, J=7.9 Hz, 2H), 6.65-6.75(m, 2H), 5.37 (q, J=6.4 Hz, 1H), 4.18-4.40 (m, 4H), 4.12 (s, 2H),3.60-3.75 (m, 1H), 2.59-2.73 (m, 2H), 2.43 (d, J=7.1 Hz, 2H), 2.16 (s,3H), 2.11-2.25 (m, 2H), 1.75-1.88 (m, 1H), 1.57 (d, J=6.4 Hz, 3H), 0.87(d, J=6.6 Hz, 6H).

Example 323-[methyl({6-[(5-phenylpentyl)oxy]-2-naphthyl}methyl)amino]propanoicacid

To methyl ({6-[(5-phenylpentyl)oxy]-2-naphthyl}methyl)amine (15 mg),acrylic acid (6.2 μl) was added. Further, methanol was added thereto togive a total volume of 390 μL, followed by stirring at 60° C. for 24hours. After concentrating the reaction mixture, the residue waspurified by preparative TLC (chloroform:methanol:aqueousammonia=80:20:4) to give an invention compound (11.2 mg) having thefollowing physical properties.

TLC: Rf 0.35 (chloroform:methanol:aqueous ammonia=80:20:4);

¹H-NMR (CD₃OD): δ 7.79 (s, 1H) 7.77 (d, J=8.51 Hz, 1H) 7.76 (d, J=8.97Hz, 1H) 7.46 (dd, J=8.51, 1.74 Hz, 1H) 7.03-7.31 (m, 7H) 4.01-4.11 (m,4H) 3.09 (t, J=7.04 Hz, 2H) 2.63 (t, J=7.50 Hz, 2H) 2.53 (s, 3H)2.48-2.57 (m, 2H) 1.77-1.93 (m, 2H) 1.63-1.77 (m, 2H) 1.43-1.62 (m, 2H).

Examples 32-01 to 32-12

The procedure of Example 32 was similarly carried out, except for usinga corresponding amine compound a substitute for methyl({6-[(5-phenylpentyl)oxy]-2-naphthyl}methyl)amine to thereby giveinvention compounds having the following physical properties.

Example 32-013-[ethyl({6-[(5-phenylpentyl)oxy]-2-naphthyl}methyl)amino]propanoic acid

TLC: Rf 0.43 (chloroform:methanol:aqueous ammonia=80:20:4);

¹H-NMR (CD₃OD): δ 7.84 (s, 1H) 7.72-7.82 (m, 2H) 7.47 (dd, J=8.42, 1.83Hz, 1H) 7.06-7.29 (m, 7H) 4.22 (s, 2H) 4.05 (t, J=6.31 Hz, 2H) 3.20 (t,J=6.86 Hz, 2H) 3.00 (q, J=7.20 Hz, 2H) 2.62 (t, J=7.50 Hz, 2H) 2.53 (t,J=6.86 Hz, 2H) 1.76-1.93 (m, 2H) 1.62-1.75 (m, 2H) 1.43-1.61 (m, 2H)1.25 (t, J=7.20 Hz, 3H).

Example 32-023-[({6-[(5-phenylpentyl)oxy]-2-naphthyl}methyl)(propyl)amino]propanoicacid

TLC: Rf 0.24 (chloroform:methanol:aqueous ammonia=80:20:4);

¹H-NMR (CD₃OD): δ 7.89 (s, 1H) 7.84 (d, J=8.78 Hz, 1H) 7.80 (d, J=9.15Hz, 1H) 7.49 (dd, J=8.42, 1.65 Hz, 1H) 7.06-7.30 (m, 7H) 4.39 (s, 2H)4.08 (t, J=6.40 Hz, 2H) 3.26-3.40 (m, 2H) 2.93-3.13 (m, 2H) 2.64 (t,J=7.68 Hz, 2H) 2.59 (t, J=6.31 Hz, 2H) 1.80-1.94 (m, 2H) 1.62-1.79 (m,4H) 1.46-1.62 (m, 2H) 0.90 (t, J=7.41 Hz, 3H).

Example 32-033-[isopropyl({6-[(5-phenylpentyl)oxy]-2-naphthyl}methyl)amino]propanoicacid

TLC: Rf 0.54 (chloroform:methanol:aqueous ammonia=80:20:4);

¹H-NMR (CD₃OD): δ 7.79 (s, 1H) 7.75 (d, J=8.60 Hz, 1H) 7.73 (d, J=9.15Hz, 1H) 7.48 (dd, J=8.60, 1.74 Hz, 1H) 7.04-7.29 (m, 7H) 4.07 (t, J=6.31Hz, 2H) 4.01-4.13 (m, 2H) 2.93-3.13 (m, 2H) 2.65 (t, J=7.50 Hz, 2H) 2.44(t, J=6.68 Hz, 2H) 1.79-1.94 (m, 2H) 1.64-1.79 (m, 2H) 1.47-1.63 (m, 2H)1.25-1.34 (m, 1H) 1.21 (d, J=6.59 Hz, 6H).

Example 32-043-[(2-hydroxyethyl)({6-[(5-phenylpentyl)oxy]-2-naphthyl}methyl)amino]propanoicacid

TLC: Rf 0.28 (chloroform:methanol:aqueous ammonia=80:10:1);

¹H-NMR (CD₃OD): δ 7.90 (s, 1H) 7.75-7.87 (m, 2H) 7.52 (dd, J=8.32, 1.74Hz, 1H) 7.05-7.30 (m, 7H) 4.46 (s, 2H) 4.09 (t, J=6.40 Hz, 2H) 3.83 (t,J=5.20 Hz, 2H) 3.37 (t, J=6.31 Hz, 2H) 3.20 (t, J=5.20 Hz, 2H) 2.65 (t,J=7.55 Hz, 2H) 2.60 (t, J=6.31 Hz, 2H) 1.80-1.95 (m, 2H) 1.64-1.79 (m,2H) 1.46-1.63 (m, 2H).

Example 32-053-{4-methoxy-4-[4-(3-phenylpropoxy)phenyl]-1-piperidinyl}propanoic acid

TLC: Rf 0.29 (chloroform:methanol:aqueous ammonia=80:20:4);

¹H-NMR (CD₃OD): δ 7.33 (d, J=8.97 Hz, 2H) 7.09-7.29 (m, 5H) 6.93 (d,J=8.97 Hz, 2H) 3.97 (t, J=6.31 Hz, 2H) 3.38-3.52 (m, 2H) 3.17-3.38 (m,4H) 2.95 (s, 3H) 2.79 (t, J=7.55 Hz, 2H) 2.57 (t, J=6.59 Hz, 2H)2.26-2.41 (m, 2H) 1.98-2.24 (m, 4H).

Example 32-06 3-{4-[4-(3-phenylpropoxy)phenyl]-1-piperidinyl}propanoicacid trifluoroacetate

TLC: Rf 0.29 (chloroform:methanol:aqueous ammonia=80:20:4);

¹H-NMR (CD₃OD): δ 7.09-7.30 (m, 7H) 6.86 (d, J=8.78 Hz, 2H) 3.93 (t,J=6.31 Hz, 2H) 3.60-3.74 (m, 2H) 3.44 (t, J=7.04 Hz, 2H) 3.06-3.23 (m,2H) 2.84 (t, J=7.04 Hz, 2H) 2.78 (t, J=7.04 Hz, 2H) 2.71-2.91 (m, 1H)1.98-2.17 (m, 4H) 1.86-1.98 (m, 2H).

Example 32-073-[5-methyl-4-[4-(3-phenylpropoxy)phenyl]-3,6-dihydropyridin-1(2H)-yl]propanoicacid

TLC: Rf 0.23 (chloroform:methanol:aqueous ammonia=80:20:4);

¹H-NMR (CD₃OD): δ 7.13-7.31 (m, 5H), 7.11 (d, J=8.78 Hz, 2H), 6.90 (d,J=8.78 Hz, 2H), 3.95 (t, J=6.22 Hz, 2H), 3.64 (s, 2H), 3.26-3.37 (m,4H), 2.79 (t, J=7.50 Hz, 2H), 2.52-2.69 (m, 4H), 1.95-2.13 (m, 2H), 1.64(s, 3H).

Example 32-08 3-{4-[4-(3-phenylpropoxy)phenyl]-1-piperadinyl}propanoicacid dihydrochloride

TLC: Rf 0.18 (chloroform:methanol:aqueous ammonia=80:20:4);

¹H-NMR (CD₃OD): δ 7.10-7.33 (m, 5H) 6.97-7.10 (m, 2H) 6.88 (d, J=7.32Hz, 2H) 3.92 (t, J=6.31 Hz, 2H) 3.52 (t, J=7.23 Hz, 2H) 3.34-3.78 (m,8H) 2.89 (t, J=7.23 Hz, 2H) 2.78 (t, J=7.59 Hz, 2H) 1.93-2.14 (m, 2H).

Example 32-093-[6-(3-phenylpropoxy)-3,4-dihydro-2(1H)-isoquinolinyl]propanoic acidhydrochloride

TLC: Rf 0.18 (chloroform:methanol:aqueous ammonia=80:20:4);

¹H-NMR (CD₃OD): δ 6.99-7.37 (m, 6H) 6.85 (dd, J=8.60, 2.74 Hz, 1H) 6.79(d, J=2.74 Hz, 1H) 4.21-4.66 (m, 2H) 3.95 (t, J=6.31 Hz, 2H) 3.55 (t,J=7.04 Hz, 2H) 3.35-3.85 (m, 2H) 3.03-3.26 (m, 2H) 2.93 (t, J=7.04 Hz,2H) 2.78 (t, J=7.59 Hz, 2H) 1.96-2.15 (m, 2H).

Example 32-103-[6-[(5-phenylpentyl)oxy]-3,4-dihydro-2(1H)-isoquinolinyl]propanoicacid hydrochloride

TLC: Rf 0.22 (chloroform:methanol:aqueous ammonia=80:20:4);

¹H-NMR (CD₃OD): δ 7.01-7.32 (m, 6H) 6.83 (dd, J=8.42, 2.56 Hz, 1H) 6.79(d, J=2.56 Hz, 1H) 4.40 (s, 2H) 3.95 (t, J=6.31 Hz, 2H) 3.51-3.68 (m,2H) 3.54 (t, J=7.04 Hz, 2H) 3.09-3.23 (m, 2H) 2.91 (t, J=7.04 Hz, 2H)2.63 (t, J=7.55 Hz, 2H) 1.73-1.90 (m, 2H) 1.59-1.73 (m, 2H) 1.36-1.59(m, 2H).

Example 32-113-{(3Z)-3-[4-(3-phenylpropoxy)benzylidene]-1-piperidinyl}propanoic acidhydrochloride

TLC: Rf 0.35 (chloroform:methanol:aqueous ammonia=80:20:4);

¹H-NMR (CD₃OD): δ 7.15-7.30 (m, 5H) 7.13 (d, J=8.78 Hz, 2H) 6.91 (d,J=8.78 Hz, 2H) 6.67 (s, 1H) 3.95 (t, J=6.31 Hz, 2H) 3.87-3.96 (m, 2H)3.31-3.35 (m, 2H) 3.21 (t, J=6.68 Hz, 2H) 2.79 (t, J=7.50 Hz, 2H)2.45-2.54 (m, 2H) 2.42 (t, J=6.68 Hz, 2H) 2.00-2.14 (m, 2H) 1.88-2.01(m, 2H).

Example 32-123-{(3E)-3-[4-(3-phenylpropoxy)benzylidene]-1-piperidinyl}propanoic acidhydrochloride

TLC: Rf 0.26 (chloroform:methanol:aqueous ammonia=80:20:4);

¹H-NMR (CD₃OD): δ 7.06-7.30 (m, 7H) 6.89 (d, J=8.78 Hz, 2H) 6.61 (s, 1H)3.96 (t, J=6.22 Hz, 2H) 3.84 (s, 2H) 3.19-3.40 (m, 4H) 2.79 (t, J=7.50Hz, 2H) 2.58-2.68 (m, 2H) 2.58 (t, J=6.68 Hz, 2H) 1.98-2.12 (m, 2H)1.79-1.96 (m, 2H).

Example 333-[(3-{4-[3-(4-methylphenyl)propoxy]phenyl}propyl)amino]propanoic acidhydrochloride

To a solution of the compound (48 mg) prepared in Example 5 intetrahydrofuran (3 mL), 3-(4-methylphenyl)propanol (19 mg), diethylazodicarboxylate (60 mg) and polymer supported triphenylphosphine (2.3mmol/g, 60 mg) were added, followed by stirring at room temperature for2 days. After filtering off insoluble matters and concentrating themixture, the residue was purified by silica gel column chromatography(hexane:ethyl acetate=3:1) to give an ether compound. To a solution ofthe obtained compound in 1,4-dioxane (2 mL), a 4N hydrogenchloride/1,4-dioxane solution (0.8 mL) was added, followed by stirringat 40° C. for 1 hour. The reaction mixture was concentrated and washedwith ethyl acetate to thereby give an invention compound (32.5 mg)having the following physical properties.

TLC: Rf 0.29 (n-butanol:acetic acid:water=20:4:1);

¹H-NMR (CD₃OD): δ 7.01-7.17 (m, 6H), 6.76-6.91 (m, 2H), 3.90 (t, J=6.31Hz, 2H), 3.24 (t, J=6.59 Hz, 2H), 2.93-3.08 (m, 2H), 2.57-2.80 (m, 6H),2.28 (s, 3H), 1.87-2.10 (m, 4H).

Example 34[6-(4-phenylbutoxy)-3,4-dihydronaphthalen-1(2H)-ylidene]acetonitrile(E/Z mixture)

To a solution of 6-(4-phenylbutoxy)-3,4-dihydronaphthalen-1(2H)-one (300mg) in tetrahydrofuran (10 mL), diethyl cyanomethylphosphonate (199 mg)and sodium hydride (60%, 97.8 mg) were added, followed by stirring atroom temperature for 24 hours. After adding water, the reaction mixturewas extracted with ethyl acetate. The organic layer was washed with asaturated aqueous sodium chloride solution, concentrated and thenpurified by silica gel column chromatography (hexane:ethyl acetate=3:1)to thereby give the title compound (E/Z mixture, 207 mg) having thefollowing physical properties.

TLC: Rf 0.68 (hexane:ethyl acetate=3:1).

Example 353-({2-[6-(4-phenylbutoxy)-3,4-dihydro-1-naphthalenyl]ethyl}amino)propanoicacid hydrochloride

To a solution of the compound (205 mg) prepared in Example 34 intetrahydrofuran (6.5 mL), a 1M diisobutyl aluminum hydride/toluenesolution (1.4 mL) was added at 0° C., followed by stirring at roomtemperature for 3 hours. After adding 2N hydrochloric acid, the reactionmixture was stirred for 15 minutes and extracted with ethyl acetate. Theorganic layer was washed with saturated aqueous sodium chloridesolution, concentrated and purified by silica gel column chromatography(hexane:ethyl acetate=3:1) to give an aldehyde compound. Then, theprocedure of Example 29 was similarly carried out, except for using thealdehyde compound thus obtained as a substitute for(2E)-3-[4-(3-phenylpropoxy)phenyl]but-2-enal to thereby give aninvention compound having the following physical properties.

TLC: Rf 0.25 (n-butanol:acetic acid:water=20:4:1);

¹H-NMR (CD₃OD): δ 7.08-7.32 (m, 6H) 6.67-6.82 (m, 2H) 5.89 (t, J=4.57Hz, 1H) 3.89-4.07 (m, 2H) 3.23-3.40 (m, 2H) 3.19 (t, J=7.50 Hz, 2H) 2.83(t, J=7.59 Hz, 2H) 2.62-2.77 (m, 6H) 2.19-2.29 (m, 2H) 1.72-1.85 (m,4H).

Examples 36-1 to 36-2

The procedures of Example 1 and Example 2 as described in WO 02/092068were followed in this order but using a corresponding amine compound asa substitute for methyl 2-methoxy-5-aminobenzoate to thereby giveinvention compounds having the following physical properties.

Example 36-1{3-[(3-{4-[(5-phenylpentyl)oxy]phenyl}propanoyl)amino]phenyl}acetic acid

HPLC retention time (minute: measurement conditions of HPLC aredescribed in Example 26): 4.31;

MS (m/z): 891 (2M+H)⁺, 446 (M+H)⁺.

Example 36-2{4-[(3-({4-[(5-phenylpentyl)oxy]phenyl}propanoyl)amino]phenyl}aceticacid

HPLC retention time (minute: measurement conditions of HPLC aredescribed in Example 26): 4.27;

MS (m/z): 891 (2M+H)⁺, 446 (M+H)⁺.

Examples 37-01 to 37-32

The procedure of Example 29 was similarly carried out, except for usinga corresponding amine compound as a substitute for β-alanine and acorresponding aldehyde compound as a substitute for(2E)-3-[4-(3-phenylpropoxy)phenyl]but-2-enal to thereby give inventioncompounds having the following physical properties.

Example 37-011-[(1-methyl-6-{[(1R,2R)-2-phenylcyclopropyl]methoxy}-3,4-dihydronaphthalen-2-yl)methyl]azetidine-3-carboxylicacid:

TLC: Rf 0.26(chloroform:methanol:aqueous ammonia=80:20:4);

¹H-NMR (CD₃OD): δ 7.31 (d, J=8.60 Hz, 1H), 7.17-7.26 (m, 2H), 7.04-7.16(m, 3H), 6.79 (dd, J=8.60, 2.74 Hz, 1H), 6.74 (d, J=2.74 Hz, 1H),4.11-4.28 (m, 4H), 4.09 (s, 2H), 3.90-4.08 (m, 2H), 3.36-3.50 (m, 1H),2.65-2.78 (m, 2H), 2.15-2.30 (m, 5H), 1.86-2.02 (m, 1H), 1.44-1.64 (m,1H), 1.03 (t, J=6.68 Hz, 2H);

Melting point: 70-84° C.

Example 37-021-({6-[3-(4-fluoro-3-methylphenyl)propoxy]-1-methyl-3,4-dihydronaphthalen-2-yl}methyl)azetidine-3-carboxylicacid

TLC: Rf 0.26(chloroform:methanol:aqueous ammonia=80:20:4);

¹H-NMR (CD₃OD): δ 7.30 (d, J=8.60 Hz, 1H), 6.95-7.10 (m, 2H), 6.81-6.94(m, 1H), 6.75 (dd, J=8.60, 2.75 Hz, 1H), 6.70 (d, J=2.75 Hz, 1H),4.11-4.27 (m, 4H), 4.08 (s, 2H), 3.94 (t, J=6.22 Hz, 2H), 3.35-3.48 (m,1H), 2.66-2.78 (m, 4H), 2.15-2.31 (m, 8H), 1.94-2.10 (m, 2H).

Melting point: 149-152° C.

Example 37-031-{[1-methyl-6-(quinolin-7-ylmethoxy)-3,4-dihydronaphthalen-2-yl]methyl}azetidine-3-carboxylicacid

TLC: Rf 0.23 (chloroform:methanol:aqueous ammonia=80:20:4);

¹H-NMR (CD₃OD): δ 8.83 (dd, J=4.5, 1.0 Hz, 1H), 8.36 (dd, J=8.5, 1.0 Hz,1H), 8.07 (s, 1H), 7.96 (d, J=8.5 Hz, 1H), 7.68 (d, J=8.5 Hz, 1H), 7.52(dd, J=8.5, 4.5 Hz, 1H), 7.33 (d, J=8.5 Hz, 1H), 6.83-6.97 (m, 2H), 5.33(s, 2H), 4.11-4.28 (m, 4H), 4.08 (s, 2H), 3.34-3.52 (m, 1H), 2.66-2.79(m, 2H), 2.13-2.28 (m, 5H).

Example 37-041-({6-[3-(2,6-difluorophenyl)propoxy]-1-methyl-3,4-dihydronaphthalen-2-yl}methyl)azetidine-3-carboxylicacid

TLC: Rf 0.23 (chloroform:methanol:aqueous ammonia=50:10:1);

¹H-NMR (CD₃OD): δ 7.31 (d, J=8.6 Hz, 1H), 7.14-7.29 (m, 1H), 6.85-6.95(m, 2H), 6.74 (dd, J=8.6, 2.6 Hz, 1H), 6.69 (d, J=2.6 Hz, 1H), 4.12-4.27(m, 4H), 4.10 (s, 2H), 3.99 (t, J=6.0 Hz, 2H), 3.34-3.52 (m, 1H), 2.87(t, J=7.3 Hz, 2H), 2.72 (t, J=7.2 Hz, 2H), 2.17-2.28 (m, 5H), 1.95-2.10(m, 2H);

Melting point: 144-150° C.

Example 37-051-[(1-methyl-6-{3-[2-(trifluoromethyl)phenyl]propoxy}-3,4-dihydronaphthalen-2-yl)methyl]azetidine-3-carboxylicacid

TLC: Rf 0.18 (chloroform:methanol:aqueous ammonia=50:10:1);

¹H-NMR (CD₃OD): δ 7.64 (d, J=7.7 Hz, 1H), 7.49-7.57 (m, 1H), 7.44 (d,J=7.8 Hz, 1H), 7.30-7.39 (m, 2H), 6.78 (dd, J=8.5, 2.7 Hz, 1H), 6.73 (d,J=2.7 Hz, 1H), 4.13-4.26 (m, 4H), 4.10 (s, 2H), 4.02 (t, J=6.2 Hz, 2H),3.34-3.50 (m, 1H), 2.98 (t, J=7.8 Hz, 2H), 2.73 (t, J=8.1 Hz, 2H),2.18-2.29 (m, 5H), 1.99-2.14 (m, 2H);

Melting point: 125-127° C.

Example 37-061-({6-[3-(3,4-dimethylphenyl)propoxy]-1-methyl-3,4-dihydronaphthalen-2-yl}methyl)azetidine-3-carboxylicacid

TLC: Rf 0.17 (chloroform:methanol:aqueous ammonia=50:10:1);

¹H-NMR (CD₃OD): δ 7.31 (d, J=8.4 Hz, 1H), 7.00 (d, J=7.5 Hz, 1H), 6.95(d, J=1.5 Hz, 1H), 6.89 (dd, J=7.5, 1.5 Hz, 1H), 6.75 (dd, J=8.4, 2.4Hz, 1H), 6.70 (d, J=2.4 Hz, 1H), 4.12-4.28 (m, 4H), 4.10 (s, 2H), 3.94(t, J=6.3 Hz, 2H), 3.33-3.49 (m, 1H), 2.66-2.76 (m, 4H), 2.15-2.28 (m,11H), 1.89-2.09 (m, 2H);

Melting point: 167-172° C.

Example 37-071-{[1-methyl-6-(1,2,3,4-tetrahydronaphthalen-2-ylmethoxy)-3,4-dihydronaphthalen-2-yl]methyl}azetidine-3-carboxylicacid

TLC: Rf 0.31 (chloroform:methanol:aqueous ammonia=80:20:4);

¹H-NMR (CD₃OD): δ 7.33 (d, J=8.50 Hz, 1H), 7.04-7.06 (m, 4H), 6.81 (dd,J=8.50, 2.50 Hz, 1H), 6.77 (d, J=2.50 Hz, 1H), 4.11-4.24 (m, 4H), 4.08(s, 2H), 3.96 (d, J=6.50 Hz, 2H), 3.35-3.47 (m, 1H), 2.96 (dd, J=16.00,5.00 Hz, 1H), 2.80-2.88 (m, 2H), 2.70-2.77 (m, 2H), 2.61 (dd, J=16.00,10.50 Hz, 1H), 2.19-2.28 (m, 6H), 2.06-2.14 (m, 1H), 1.53-1.64 (m, 1H).

Example 37-081-({6-[(4′-fluoro-1,1′-biphenyl-4-yl)methoxy]-1-methyl-3,4-dihydronaphthalen-2-yl}methyl)azetidine-3-carboxylicacid

TLC: Rf 0.29 (chloroform:methanol:aqueous ammonia=80:20:4);

¹H-NMR (DMSO-d₆): δ 7.63-7.73 (m, 4H), 7.51 (d, J=8.00 Hz, 2H), 7.28 (t,J=9.00 Hz, 2H), 7.17 (d, J=9.50 Hz, 1H), 6.81-6.85 (m, 2H), 5.13 (s,2H), 3.13-3.56 (m, 7H), 2.53-2.65 (m, 2H), 2.10-2.21 (m, 2H), 2.01 (s,3H).

Example 37-091-({6-[3,3-bis(4-fluorophenyl)propoxy]-1-methyl-3,4-dihydronaphthalen-2-yl}methyl)azetidine-3-carboxylicacid

TLC: Rf 0.32 (chloroform:methanol:aqueous ammonia=80:20:4);

¹H-NMR (CD₃OD): δ 7.25-7.32 (m, 5H), 6.99 (t, J=9.00 Hz, 4H), 6.69 (dd,J=8.50, 2.50 Hz, 1H), 6.65 (d, J=2.50 Hz, 1H), 4.14-4.31 (m, 5H), 4.10(s, 2H), 3.87 (t, J=6.00 Hz, 2H), 3.38-3.49 (m, 1H), 2.66-2.74 (m, 2H),2.42-2.51 (m, 2H), 2.17-2.27 (m, 5H).

Example 37-101-{[1-methyl-6-(5-phenylpentyloxy)-3,4-dihydro-2-naphthalenyl]methyl}-3-azetidinecarboxylicacid

TLC: Rf 0.25 (chloroform:methanol:aqueous ammonia=80:20:4)

¹H-NMR (CD₃OD): δ 7.30 (d, J=8.50 Hz, 1H), 7.20-7.27 (m, 2H), 7.09-7.19(m, 3H), 6.74 (dd, J=8.50, 2.50 Hz, 1H), 6.70 (d, J=2.50 Hz, 1H),4.12-4.26 (m, 4H), 4.09 (s, 2H), 3.96 (t, J=6.50 Hz, 2H), 3.36-3.49 (m,1H), 2.67-2.76 (m, 2H), 2.63 (t, J=8.00 Hz, 2H), 2.17-2.28 (m, 5H),1.73-1.84 (m, 2H), 1.62-1.72 (m, 2H), 1.43-1.55 (m, 2H);

Melting point: 129-133° C.

Example 37-111-[(6-{3-[4-chloro-2-(trifluoromethyl)phenyl]propoxy}-1-methyl-3,4-dihydronaphthalen-2-yl)methyl]azetidine-3-carboxylicacid

TLC: Rf 0.24(chloroform:methanol:aqueous ammonia=80:20:4);

¹H-NMR (CD₃OD): δ 7.64 (d, J=2.56 Hz, 1H), 7.55 (dd, J=8.23, 2.56 Hz,1H), 7.46 (d, J=8.23 Hz, 1H), 7.32 (d, J=8.23 Hz, 1H), 6.77 (dd, J=8.23,2.74 Hz, 1H), 6.72 (d, J=2.74 Hz, 1H), 4.09-4.24 (m, 4H), 4.06 (s, 2H),4.03 (t, J=6.04 Hz, 2H), 3.33-3.49 (m, 1H), 2.88-3.03 (m, 2H), 2.64-2.79(m, 2H), 2.16-2.30 (m, 5H), 1.98-2.14 (m, 2H);

Melting point: 127-128° C.

Example 37-121-{[6-(1,1′-biphenyl-3-ylmethoxy)-1-methyl-3,4-dihydronaphthalen-2-yl]methyl}azetidine-3-carboxylicacid hydrochloride

TLC: Rf 0.15 (n-butanol:acetic acid:water=20:4:1);

¹H-NMR (CD₃OD): δ 7.67 (s, 1H), 7.54-7.62 (m, 3H), 7.39-7.47 (m, 4H),7.30-7.36 (m, 2H), 6.89 (dd, J=8.70, 2.38 Hz, 1H), 6.85 (d, J=2.38 Hz,1H), 5.17 (s, 2H), 4.21-4.43 (m, 4H), 4.16 (s, 2H), 3.63-3.81 (m, 1H),2.69-2.78 (m, 2H), 2.14-2.30 (m, 5H);

Melting point: 119-120° C.

Example 37-131-[(6-{3-[2,5-bis(trifluoromethyl)phenyl]propoxy}-1-methyl-3,4-dihydronaphthalen-2-yl)methyl]azetidine-3-carboxylicacid

TLC: Rf 0.25(chloroform:methanol:aqueous ammonia=80:20:4);

¹H-NMR (CD₃OD): δ 7.87 (d, J=8.23 Hz, 1H), 7.77 (s, 1H), 7.68 (d, J=8.23Hz, 1H), 7.32 (d, J=8.60 Hz, 1H), 6.77 (dd, J=8.60, 2.38 Hz, 1H), 6.72(d, J=2.38 Hz, 1H), 4.12-4.27 (m, 4H), 4.09 (s, 2H), 4.04 (t, J=5.95 Hz,2H), 3.35-3.48 (m, 1H), 3.03-3.11 (m, 2H), 2.69-2.77 (m, 2H), 2.20-2.29(m, 5H), 2.03-2.17 (m, 2H);

Melting point: 119-124° C.

Example 37-141-({1-methyl-6-[3-(2,4,5-trifluorophenyl)propoxy]-3,4-dihydronaphthalen-2-yl}methyl)azetidine-3-carboxylicacid

TLC: Rf 0.26(chloroform:methanol:aqueous ammonia=80:20:4);

¹H-NMR (CD₃OD): δ 7.30 (d, J=8.60 Hz, 1H), 7.14-7.26 (m, 1H), 7.02-7.13(m, 1H), 6.75 (dd, J=8.60, 2.56 Hz, 1H), 6.70 (d, J=2.56 Hz, 1H),4.04-4.22 (m, 4H), 4.02 (s, 2H), 3.98 (t, J=6.04 Hz, 2H), 3.32-3.46 (m,1H), 2.80 (t, J=7.59 Hz, 2H), 2.66-2.75 (m, 2H), 2.15-2.29 (m, 5H),1.96-2.11 (m, 2H);

Melting point: 159-164° C.

Example 37-151-[(6-{3-[4-fluoro-3-(trifluoromethyl)phenyl]propoxy}-1-methyl-3,4-dihydronaphthalen-2-yl)methyl]azetidine-3-carboxylicacid

TLC: Rf 0.29(chloroform:methanol:aqueous ammonia=80:20:4);

¹H-NMR (CD₃OD): δ 7.45-7.55 (m, 2H), 7.31 (d, J=8.60 Hz, 1H), 7.21 (t,J=10.43 Hz, 1H), 6.77 (dd, J=8.60, 2.65 Hz, 1H), 6.70 (d, J=2.65 Hz,1H), 4.11-4.27 (m, 4H), 4.08 (s, 2H), 3.97 (t, J=6.13 Hz, 2H), 3.33-3.50(m, 1H), 2.80-2.91 (m, 2H), 2.66-2.78 (m, 2H), 2.16-2.29 (m, 5H),2.00-2.13 (m, 2H).

Example 37-161-[(6-{3-[4-fluoro-2-(trifluoromethyl)phenyl]propoxy}-1-methyl-3,4-dihydronaphthalen-2-yl)methyl]azetidine-3-carboxylicacid

TLC: Rf 0.26(chloroform:methanol:aqueous ammonia=80:20:4);

¹H-NMR (CD₃OD): δ 7.48 (dd, J=8.60, 5.49 Hz, 1H), 7.39 (dd, J=9.24, 2.65Hz, 1H), 7.24-7.34 (m, 2H), 6.77 (dd, J=8.60, 2.56 Hz, 1H), 6.72 (d,J=2.56 Hz, 1H), 4.11-4.27 (m, 4H), 4.08 (s, 2H), 4.02 (t, J=6.04 Hz,2H), 3.33-3.49 (m, 1H), 2.90-3.03 (m, 2H), 2.66-2.78 (m, 2H), 2.16-2.32(m, 5H), 1.93-2.13 (m, 2H);

Melting point: 126-128° C.

Example 37-171-({1-methyl-6-[3-(2,3,4-trifluorophenyl)propoxy]-3,4-dihydronaphthalen-2-yl}methyl)azetidine-3-carboxylicacid

TLC: Rf 0.25(chloroform:methanol:aqueous ammonia=80:20:4);

¹H-NMR (DMSO-d₆): δ 7.09-7.30 (m, 3H), 6.65-6.75 (m, 2H), 3.94 (t,J=6.13 Hz, 2H), 3.38 (s, 2H), 3.09-3.22 (m, 5H), 2.78 (t, J=7.50 Hz,2H), 2.53-2.62 (m, 2H), 2.10-2.19 (m, 2H), 1.92-2.04 (m, 5H);

Melting point: 151-155° C.

Example 37-181-({1-methyl-6-[3-(3,4,5-trifluorophenyl)propoxy]-3,4-dihydronaphthalen-2-yl}methyl)azetidine-3-carboxylicacid

TLC: Rf 0.29 (chloroform:methanol:aqueous ammonia=80:20:4); δ

¹H-NMR (CD₃OD): δ 7.31 (d, J=8.42 Hz, 1H), 6.93-7.03 (dd, J=9.00, 7.00Hz, 2H), 6.76 (dd, J=8.42, 2.74 Hz, 1H), 6.71 (d, J=2.74 Hz, 1H),4.09-4.26 (m, 4H), 4.07 (s, 2H), 3.97 (t, J=6.04 Hz, 2H), 3.33-3.51 (m,1H), 2.75-2.84 (m, 2H), 2.72 (t, J=8.41 Hz, 2H), 2.17-2.29 (m, 5H),1.98-2.13 (m, 2H);

Melting point: 140-144° C.

Example 37-191-({6-[3-(4-fluoro-2,6-dimethylphenyl)propoxy]-1-methyl-3,4-dihydronaphthalen-2-yl}methyl)azetidine-3-carboxylicacid

TLC: Rf 0.24(chloroform:methanol:aqueous ammonia=80:20:4);

¹H-NMR (CD₃OD): δ 7.32 (d, J=8.60 Hz, 1H), 6.78 (dd, J=8.60, 2.84 Hz,1H), 6.74 (d, J=2.84 Hz, 1H), 6.71 (d, J=9.15 Hz, 2H), 4.11-4.25 (m,4H), 4.07 (s, 2H), 4.02 (t, J=5.85 Hz, 2H), 3.35-3.49 (m, 1H), 2.77-2.86(m, 2H), 2.69-2.76 (m, 2H), 2.31 (s, 6H), 2.17-2.28 (m, 5H), 1.81-1.98(m, 2H);

Melting point: 144-146° C.

Example 37-201-({6-[3-(3-chloro-4-fluorophenyl)propoxy]-1-methyl-3,4-dihydronaphthalen-2-yl}methyl)azetidine-3-carboxylicacid

TLC: Rf 0.25(chloroform:methanol:aqueous ammonia=80:20:4);

¹H-NMR (CD₃OD): δ 7.27-7.34 (m, 2H), 7.05-7.20 (m, 2H), 6.75 (dd,J=8.51, 2.65 Hz, 1H), 6.70 (d, J=2.65 Hz, 1H), 4.11-4.27 (m, 4H), 4.08(s, 2H), 3.96 (t, J=6.13 Hz, 2H), 3.34-3.48 (m, 1H), 2.67-2.83 (m, 4H),2.20-2.29 (m, 5H), 1.98-2.10 (m, 2H);

Melting point: 118-119° C.

Example 37-211-({6-[3-(4-chloro-3-fluorophenyl)propoxy]-1-methyl-3,4-dihydronaphthalen-2-yl}methyl)azetidine-3-carboxylicacid

TLC: Rf 0.26(chloroform:methanol:aqueous ammonia=80:20:4);

¹H-NMR (CD₃OD): δ 7.30-7.37 (m, 2H), 7.10 (dd, J=10.43, 2.01 Hz, 1H),7.02 (dd, J=7.96, 2.01 Hz, 1H), 6.75 (dd, J=8.60, 2.65 Hz, 1H), 6.71 (d,J=2.65 Hz, 1H), 4.10-4.26 (m, 4H), 4.07 (s, 2H), 3.97 (t, J=6.22 Hz,2H), 3.36-3.50 (m, 1H), 2.77-2.86 (m, 2H), 2.66-2.76 (m, 2H), 2.16-2.30(m, 5H), 1.99-2.12 (m, 2H);

Melting point: 126-128° C.

Example 37-221-({6-[3-(4-chloro-2-fluorophenyl)propoxy]-1-methyl-3,4-dihydronaphthalen-2-yl}methyl)azetidine-3-carboxylicacid

TLC: Rf 0.24(chloroform:methanol:aqueous ammonia=80:20:4);

¹H-NMR (CD₃OD): δ 7.31 (d, J=8.42 Hz, 1H), 7.24 (t, J=8.42 Hz, 1H),7.06-7.16 (m, 2H), 6.75 (dd, J=8.42, 2.47 Hz, 1H), 6.70 (d, J=2.47 Hz,1H), 4.10-4.27 (m, 4H), 4.07 (s, 2H), 3.97 (t, J=6.13 Hz, 2H), 3.35-3.50(m, 1H), 2.78-2.87 (m, 2H), 2.67-2.76 (m, 2H), 2.15-2.32 (m, 5H),1.96-2.12 (m, 2H);

Melting point: 160-162° C.

Example 37-231-[(6-{3-[4-chloro-3-(trifluoromethyl)phenyl]propoxy}-1-methyl-3,4-dihydronaphthalen-2-yl)methyl]azetidine-3-carboxylicacid hydrochloride

TLC: Rf 0.20 (n-butanol:acetic acid:water=20:4:1)

¹H-NMR (CD₃OD): δ 7.60 (d, J=1.10 Hz, 1H), 7.41-7.53 (m, 2H), 7.32 (d,J=8.60 Hz, 1H), 6.75 (dd, J=8.60, 2.38 Hz, 1H), 6.70 (d, J=2.38 Hz, 1H),4.20-4.45 (m, 4H), 4.16 (s, 2H), 3.98 (t, J=6.04 Hz, 2H), 3.59-3.78 (m,1H), 2.88 (t, J=7.80 Hz, 2H), 2.67-2.77 (m, 2H), 2.18-2.30 (m, 5H),2.00-2.14 (m, 2H);

Melting point: 120-124° C.

Example 37-241-({6-[3-(2-chloro-4-fluorophenyl)propoxy]-1-methyl-3,4-dihydronaphthalen-2-yl}methyl)azetidine-3-carboxylicacid hydrochloride

TLC: Rf 0.17 (n-butanol:acetic acid:water=20:4:1)

¹H-NMR (CD₃OD): δ 7.26-7.36 (m, 2H), 7.17 (dd, J=8.78, 2.74 Hz, 1H),6.98 (td, J=8.42, 2.74 Hz, 1H), 6.77 (dd, J=8.40, 2.38 Hz, 1H), 6.72 (d,J=2.38 Hz, 1H), 4.21-4.41 (m, 4H), 4.16 (s, 2H), 3.99 (t, J=6.13 Hz,2H), 3.62-3.77 (m, 1H), 2.91 (t, J=7.50 Hz, 2H), 2.73 (t, J=6.30 Hz,2H), 2.19-2.29 (m, 5H), 2.00-2.12 (m, 2H);

Melting point: 125-127° C.

Example 37-251-({6-[3-(2-chloro-3,6-difluorophenyl)propoxy]-1-methyl-3,4-dihydronaphthalen-2-yl}methyl)azetidine-3-carboxylicacid

TLC: Rf 0.23(chloroform:methanol:aqueous ammonia=80:20:4);

¹H-NMR (DMSO-d₆): δ 7.35 (td, J=9.01, 4.94 Hz, 1H), 7.26 (td, J=9.01,4.67 Hz, 1H), 7.14 (d, J=8.23 Hz, 1H), 6.65-6.72 (m, 2H), 3.97 (t,J=5.95 Hz, 2H), 3.38 (s, 2H), 3.13-3.20 (m, 5H), 2.86-2.97 (m, 2H),2.52-2.62 (m, 2H), 2.09-2.20 (m, 2H), 1.89-2.00 (m, 5H);

Melting point: 156-159° C.

Example 37-261-({1-methyl-6-[3-(2,4,6-trifluorophenyl)propoxy]-3,4-dihydronaphthalen-2-yl}methyl)azetidine-3-carboxylicacid

TLC: Rf 0.21(chloroform:methanol:aqueous ammonia=80:20:4);

¹H-NMR (CD₃OD): δ 7.30 (d, J=8.50 Hz, 1H), 6.80 (dd, J=9.00, 8.00 Hz,2H), 6.73 (dd, J=8.50, 2.50 Hz, 1H), 6.68 (d, J=2.50 Hz, 1H), 4.11-4.25(m, 4H), 4.07 (s, 2H), 3.98 (t, J=6.00 Hz, 2H), 3.35-3.48 (m, 1H), 2.84(t, J=7.50 Hz, 2H), 2.68-2.76 (m, 2H), 2.18-2.28 (m, 5H), 1.97-2.08 (m,2H);

Melting point: 159-162° C.

Example 37-271-{[6-(2,2-dimethyl-3-phenylpropoxy)-1-methyl-3,4-dihydronaphthalen-2-yl]methyl}azetidine-3-carboxylicacid hydrochloride

TLC: Rf 0.19 (n-butanol:acetic acid:water=20:4:1)

¹H-NMR (CD₃OD): δ 7.34 (d, J=8.23 Hz, 1H), 7.03-7.26 (m, 5H), 6.70-6.85(m, 2H), 4.20-4.50 (m, 4H), 4.17 (s, 2H), 3.60-3.81 (m, 1H), 3.54 (s,2H), 2.67-2.81 (m, 4H), 2.20-2.32 (m, 5H), 1.01 (s, 6H);

Melting point: 124-127° C.

Example 37-281-({1-methyl-6-[2-(1,2,3,4-tetrahydronaphthalen-1-yl)ethoxy]-3,4-dihydronaphthalen-2-yl}methyl)azetidine-3-carboxylicacid

TLC: Rf 0.37(chloroform:methanol:aqueous ammonia=80:20:4);

¹H-NMR (CD₃OD): δ 7.33 (d, J=8.50 Hz, 1H), 7.09-7.15 (m, 1H), 7.01-7.08(m, 3H), 6.79 (dd, J=8.50, 2.50 Hz, 1H), 6.74 (d, J=2.50 Hz, 1H),4.03-4.25 (m, 8H), 3.34-3.49 (m, 1H), 3.01-3.10 (m, 1H), 2.69-2.80 (m,4H), 2.09-2.29 (m, 6H), 1.70-2.03 (m, 5H);

Melting point: 99-107° C.

Example 37-291-({6-[2-(2,3-dihydro-1H-inden-1-yl)ethoxy]-1-methyl-3,4-dihydronaphthalen-2-yl}methyl)azetidine-3-carboxylicacid

TLC: Rf 0.32(chloroform:methanol:aqueous ammonia=80:20:4);

¹H-NMR (CD₃OD): δ 7.33 (d, J=8.50 Hz, 1H), 7.16-7.22 (m, 2H), 7.08-7.13(m, 2H), 6.79 (dd, J=8.50, 2.50 Hz, 1H), 6.75 (d, J=2.50 Hz, 1H),4.14-4.25 (m, 4H), 4.07-4.14 (m, 4H), 3.35-3.48 (m, 1H), 3.28-3.32 (m,1H), 2.69-3.01 (m, 4H), 2.19-2.39 (m, 7H), 1.71-1.91 (m, 2H);

Melting point: 163-167° C.

Example 37-301-({6-[2-(5-fluoro-2,3-dihydro-1H-inden-1-yl)ethoxy]-1-methyl-3,4-dihydronaphthalen-2-yl}methyl)azetidine-3-carboxylicacid

TLC: Rf 0.29(chloroform:methanol:aqueous ammonia=80:20:4);

¹H-NMR (CD₃OD): δ 7.32 (d, J=8.50 Hz, 1H), 7.16 (dd, J=8.50, 5.00 Hz,1H), 6.91 (dd, J=9.00, 2.50 Hz, 1H), 6.76-6.87 (m, 2H), 6.74 (d, J=2.50Hz, 1H), 4.05-4.24 (m, 8H), 3.34-3.47 (m, 1H), 3.28-3.32 (m, 1H),2.69-3.02 (m, 4H), 2.19-2.43 (m, 7H), 1.76-1.92 (m, 2H);

Melting point: 149-153° C.

Example 37-311-({6-[2-(4-isobutylphenyl)ethyl]-1-methyl-3,4-dihydronaphthalen-2-yl}methyl)azetidine-3-carboxylicacid hydrochloride

TLC: Rf 0.19 (n-butanol:acetic acid:water=20:4:1)

¹H-NMR (CD₃OD): δ 7.29 (d, J=7.87 Hz, 1H), 6.99-7.10 (m, 5H), 6.94 (s,1H), 4.24-4.46 (m, 4H), 4.17 (s, 2H), 3.53-3.86 (m, 1H), 2.84-2.86 (m,4H), 2.63-2.75 (m, 2H), 2.41 (d, J=7.14 Hz, 2H), 2.15-2.30 (m, 5H),1.68-1.90 (m, 1H), 0.87 (d, J=6.77 Hz, 6H);

Melting point: 154-157° C.

Example 37-321-{[9-methyl-3-(4-phenylbutoxy)-6,7-dihydro-5H-benzo[7]annulen-8-yl]methyl}azetidine-3-carboxylicacid

TLC: Rf 0.42(chloroform:methanol:aqueous ammonia=80:20:4);

MS (m/z): 420 (M+H)⁺, 319, 187.

Reference Example 01 6-(benzyloxy)-3,4-dihydronaphthalen-1(2H)-one

To a solution of 6-hydroxy-3,4-dihydronaphthalen-1(2H)-one (24.3 g) inacetone (160 mL), benzyl bromide (29.4 mL) and potassium carbonate (31.1g) were added at room temperature, followed by stirring at 40° C. for3.5 hours. After filtering off the insoluble matters and concentratingthe mixture, the residue was washed with a mixed solvent of tert-butylmethyl ether-hexane (1:4) to thereby give the title compound (34.5 g)having the following physical properties.

TLC: Rf 0.38 (hexane:ethyl acetate=3:1).

Reference Example 02 7-(benzyloxy)-4-methyl-1,2-dihydronaphthalene

To a solution of the compound (34.5 g) prepared in Reference Example 01in tetrahydrofuran (300 mL), methyl magnesium bromide (3 M diethyl ethersolution, 55 mL) was added at 0° C., followed by stirring at roomtemperature for 1 hour. Then, the reaction mixture was cooled to 0° C.and poured into ice-saturated aqueous ammonium chloride. After adding 2N hydrochloric acid, the mixture was stirred at room temperature for 3hours. Then, the mixture was extracted with ethyl acetate and theorganic layer was successively washed with water and a saturated aqueoussodium chloride solution, dried and concentrated. The residue thusobtained was purified by silica gel column chromatography (hexane:ethylacetate=10:1) to thereby give the title compound (24.8 g) having thefollowing physical properties.

TLC: Rf 0.57 (hexane:ethyl acetate=15:1).

Reference Example 036-(benzyloxy)-1-methyl-3,4-dihydronaphthalene-2-carboaldehyde

To phosphorus oxychloride (26.7 g), N,N-dimethylformamide (60 mL) wasdropped at 0° C., followed by stirring for 20 minutes. Then, a solutionof the compound (24.8 g) prepared in Reference Example 02 indichloromethane (60 mL) was slowly added dropwise thereto, followed bystirring at room temperature for 90 minutes. The reaction mixture wascooled to 0° C., poured into ice and then allowed to stand for a while.Next, the mixture was extracted with a mixed solvent of hexane-ethylacetate (1:2). The organic layer was successively washed with water anda saturated aqueous sodium chloride solution, dried and concentrated.The solid thus obtained was washed with tert-butyl methyl ether tothereby give the title compound (19.9 g) having the following physicalproperties.

TLC: Rf 0.50 (hexane:ethyl acetate=3:1).

Reference Example 046-hydroxy-1-methyl-3,4-dihydronaphthalene-2-carboaldehyde

To thioanisole (35 mL), trifluoroacetic acid (140 mL) was added at 0° C.Then, the compound (9.17 g) prepared in Reference Example 03 was addedin portions thereto, followed by stirring at room temperature for 4hours. The reaction mixture was poured into ice and then a 5 N aqueoussodium hydroxide solution was added. After washing tert-butyl methylether, 1 N hydrochloric acid was added to the aqueous layer, followed byextraction with ethyl acetate. The organic layer was dried andconcentrated. The obtained residue was purified by silica gel columnchromatography (hexane:ethyl acetate=5:1 to 2:1) to thereby give thetitle compound (6.03 g) having the following physical properties.

TLC: Rf 0.26 (hexane:ethyl acetate=3:1).

Reference Example 056-[3-(4-fluorophenyl)propoxy]-1-methyl-3,4-dihydronaphthalene-2-carboaldehyde

The procedure of Reference Example 01 was similarly carried out, exceptfor using the compound prepared in Reference Example 04 as a substitutefor 6-hydroxy-3,4-dihydronaphthalen-1(2H)-one and1-bromo-3-(4-fluorophenyl)propane as a substitute for benzyl bromide tothereby give the title compound having the following physicalproperties.

TLC: Rf 0.40 (hexane:ethyl acetate=3:1);

¹H-NMR (CDCl₃): δ 10.32 (s, 1H), 7.48 (d, J=8.50 Hz, 1H), 7.16 (dd,J=8.50, 5.50 Hz, 2H), 6.97 (t, J=8.50 Hz, 2H), 6.78 (dd, J=8.50, 2.50Hz, 1H), 6.73 (d, J=2.50 Hz, 1H), 3.99 (t, J=6.00 Hz, 2H), 2.79 (t,J=7.50 Hz, 2H), 2.69-2.75 (m, 2H), 2.47-2.56 (m, 5H), 2.04-2.14 (m, 2H).

Reference Example 06 5-oxo-5,6,7,8-tetrahydronaphthalen-2-yltrifluoromethanesulfonate

To a solution of 6-hydroxy-3,4-dihydronaphthalen-1(2H)-one (2.0 g) indichloromethane (20 mL), triethylamine (5.16 mL) andtrifluoromethanesulfonic anhydride (2.49 mL) were added at −78° C.,followed by stirring at 0° C. for 1 hour. After adding a saturatedaqueous sodium hydrogencarbonate solution, the mixture was stirred andextracted with diethyl ether. The organic layer was successively washedwith 1 N hydrochloric acid, a saturated aqueous sodium hydrogencarbonatesolution and a saturated aqueous sodium chloride solution, dried andconcentrated. The residue thus obtained was purified by silica gelcolumn chromatography (hexane:ethyl acetate=9:1) to thereby give thetitle compound (2.34 g) having the following physical properties.

TLC: Rf 0.34 (hexane:ethyl acetate=85:15).

Reference Example 076-[(4-isobutylphenyl)ethynyl]-3,4-dihydronaphthalen-1(2H)-one

To cuprous iodide (48 mg), a solution of the compound (353 mg) preparedin Reference Example 06 in N,N-dimethylformamide (3 mL), triethylamine(279 μl) and a solution of 1-ethynyl-4-isobutylbenzene (158 mg) inN,N-dimethylformamide (5 mL) were added, followed by stirring at roomtemperature for 5 minutes. Next, tetrakis(triphenylphosphine) palladium(0) (58 mg) was added thereto, followed by stirring for 19 hours. Afteradding 1 N hydrochloric acid, the mixture was extracted with ethylacetate. The organic layer was successively washed with 1 N hydrochloricacid, a saturated aqueous sodium hydrogencarbonate solution and asaturated aqueous sodium chloride solution, dried and concentrated. Theresidue thus obtained was purified by silica gel column chromatography(hexane:ethyl acetate=95:5) to thereby give the title compound (209 mg)having the following physical properties.

TLC: Rf 0.35 (hexane:ethyl acetate=9:1).

Reference Example 086-[(4-isobutylphenyl)ethynyl]-1-methyl-1,2,3,4-tetrahydronaphthalen-1-ol

To a solution of the compound (200 mg) prepared in Reference Example 07in tetrahydrofuran (5 mL), methyl magnesium bromide (3 M diethyl ethersolution, 0.33 mL) was added at 0° C., followed by stirring for 30minutes. After adding water, the reaction mixture was extracted withethyl acetate. The organic layer was washed with a saturated aqueoussodium chloride solution, dried and concentrated. The residue thusobtained was purified by silica gel column chromatography (hexane:ethylacetate=87:13) to thereby give the title compound (154 mg) having thefollowing physical properties.

TLC: Rf 0.36 (hexane:ethyl acetate=4:1).

Reference Example 096-[(4-isobutylphenyl)ethyl]-1-methyl-1,2,3,4-tetrahydronaphthalen-1-ol

To a solution of the compound (150 mg) prepared in Reference Example 08in ethanol (4 mL), 10% palladium on carbon (15 mg) was added, followedby stirring under a hydrogen gas stream for 15 minutes. After filteringoff the catalyst through Celite, the filtrate was concentrated tothereby give the title compound (153 mg) having the following physicalproperties.

TLC: Rf 0.40 (hexane:ethyl acetate=4:1).

Reference Example 107-[2-(4-isobutylphenyl)ethyl]-4-methyl-1,2-dihydronaphthalene

To a solution of the compound (150 mg) prepared in Reference Example 09in dichloromethane (3 mL), p-toluenesulfonic acid monohydrate (1 mg) wasadded, followed by stirring at room temperature for 2 hours. Thereaction mixture was concentrated and purified by silica gel columnchromatography (hexane) to thereby give the title compound (129 mg)having the following physical properties.

TLC: Rf 0.35 (hexane).

Reference Example 116-[2-(4-isobutylphenyl)ethyl]-1-methyl-3,4-dihydronaphthalene-2-carboaldehyde

The procedure of Reference Example 03 was similarly carried out, exceptfor using the compound prepared in Reference Example 10 as a substitutefor the compound prepared in Reference Example 02 to thereby give thetitle compound having the following physical properties.

TLC: Rf 0.66 (hexane:ethyl acetate=3:1);

¹H-NMR (CDCl₃): δ 10.35 (s, 1H), 7.46 (d, J=7.87 Hz, 1H), 7.00-7.14 (m,6H), 2.90 (s, 4H), 2.71 (t, J=7.32 Hz, 2H), 2.42-2.56 (m, 7H), 1.76-1.93(m, 1H), 0.90 (d, J=6.59 Hz, 6H).

Reference Example 12 3-(methoxymethoxy)benzaldehyde

To a solution of 3-hydroxybenzaldehyde (5.0 g) in acetone (120 mL),potassium carbonate (8.5 g) and methoxymethyl chloride (4.0 g) wereadded, followed by stirring at 50° C. for 6 hours. The reaction mixturewas concentrated and water was added thereto, followed by extractionwith ethyl acetate. The organic layer was washed with a saturatedaqueous sodium chloride solution, dried and concentrated. The residuethus obtained was purified by silica gel column chromatography(hexane:ethyl acetate=10:1) to thereby give the title compound (6.0 g)having the following physical properties.

TLC: Rf 0.56(hexane:ethyl acetate=3:1).

Reference Example 13 ethyl 5-(3-hydroxyphenyl)pentanoate

To a solution of vinyl magnesium bromide (1 M tetrahydrofuran solution,24.4 mL) in tetrahydrofuran (50 mL), the compound (2.7 g) prepared inReference Example 12 was added at −20° C., followed by stirring for 1hour. After adding water, the reaction mixture was concentrated.Further, a saturated aqueous ammonium chloride solution was addedthereto and the mixture was extracted with ethyl acetate. The organiclayer was washed with a saturated aqueous sodium chloride solution,dried and concentrated. To a solution of the obtained residue in toluene(50 mL), triethyl orthoacetate (14.9 mL) and propionic acid (122 μL)were added, followed by stirring at 130° C. for 2 hours. The reactionmixture was concentrated and the obtained residue was purified by silicagel column chromatography (hexane:ethyl acetate=9:1). To a solution ofthe compound thus obtained in methanol (60 mL), 10% palladium on carbon(285 mg) was added, followed by stirring under a hydrogen gas stream for2 hours. After filtering off the catalyst through Celite, the filtratewas concentrated. To a solution of the compound thus obtained in ethanol(40 mL), conc. hydrochloric acid (4 mL) was added, followed by stirringat 70° C. for 1 hour. By concentrating the reaction mixture, the titlecompound (2.37 g) having the following physical properties was obtained.

TLC: Rf 0.37 (hexane:ethyl acetate=3:1).

Reference Example 14 5-[3-(4-phenylbutoxy)phenyl]pentanoic acid

The procedure of Reference Example 01 was similarly carried out, exceptfor using the compound (1.13 g) prepared in Reference Example 13 as asubstitute for 6-hydroxy-3,4-dihydronaphthalen-1(2H)-one while using1-bromo-4-phenylbutane (1.63 g) as a substitute for benzyl bromide. Asolution of the compound thus obtained in a mixed solvent of methanol (2mL)-tetrahydrofuran (10 mL), 5 N sodium hydroxide (10 mL) was added,followed by stirring for 3 days. After adding 5 N hydrochloric acid, themixture was extracted with dichloromethane. The organic layer was driedand concentrated to thereby give the title compound (1.45 g) having thefollowing physical properties.

TLC: Rf 0.56 (hexane:ethyl acetate=1:1).

Reference Example 152-(4-phenylbutoxy)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-one

To a solution of the compound (100 mg) prepared in Reference Example 14in dichloromethane (1 mL), a catalytic amount of N,N-dimethylformamideand oxalyl chloride (40 μL) were added, followed by stirring for 30minutes. The reaction mixture was concentrated. To a solution of theresidue thus obtained in toluene (2 mL), stannic chloride (43 μL) wasadded, followed by stirring at room temperature for 1 hour. After addingwater, the reaction mixture was extracted with ethyl acetate. Theorganic layer was dried and concentrated and the obtained residue waspurified by silica gel column chromatography (hexane:ethyl acetate=8:1to 6:1) to thereby give the title compound (88 mg) having the followingphysical properties.

TLC: Rf 0.34 (hexane:ethyl acetate=6:1).

Reference Example 169-methyl-3-(4-phenylbutoxy)-6,7-dihydro-5H-benzo[7]annulene-8-carboaldehyde

The procedures of Reference Example 2 and Reference Example 3 werefollowed in this order but using the compound prepared in ReferenceExample 15 as a substitute for the compound prepared in ReferenceExample 1 to thereby give the title compound having the followingphysical properties.

TLC: Rf 0.47 (hexane:ethyl acetate=6:1).

Biological Examples

The pharmacological action of the present invention compounds have beenconfirmed by the following Biological Examples. All operations werecarried out by conventional methods by preparing gene-highly expressingcells based on the fundamental genetic engineering techniques. Also, themeasuring methods in the present invention for evaluating the compoundsof the present invention were carried out, for example, by improvingmeasuring methods, measuring accuracy and/or measuring sensitivity. Thedetails are described below. The preparation of histological preparationwas also carried out by conventional methods based on the fundamentalgenetic engineering techniques with an appropriate modification.

Biological Example 1 Measurement of Inhibitory Activity of the PresentInvention Compound on Binding of [³H]-S1P to EDG-6 Method:

Firstly, EDG-6-overexpressing cells were seeded at a density of 2×10⁵cells/well into a 12-well plate. After 12 hours, the cells were washedwith 0.5 mL of an assay buffer twice. In a saturation binding test fordetermining the K_(D) value and the B_(max) value, the cells wereincubated in 0.4 mL of an assay buffer containingD-erythro-sphingosine-3-[³H]-1-phosphate at various concentrations and 2μL of 0.01 N NaOH for 60 minutes on ice. Then, the wells were washedwith 0.8 mL of the assay buffer twice and the whole cells were disruptedby adding 0.1 mL of 0.5% TCA (trichloroacetic acid), 0.4 mL of a lysisbuffer (2% Na₂CO₃, 4% NaOH, 0.1% SDS) and 0.1 mL of 1 N hydrochloricacid. Then, 0.5 mL of the lysed solution was collected in a glass vial(Packard) with a pipette. After adding 7 mL of ACSII (Amersham), themixture was thoroughly stirred and the radioactivity was measured with aliquid scintillation counter (TRI-CARB 2900TR Packard), therebydetermining the K_(D) value. The value of the nonspecific binding wasdetermined by adding unlabeled S1P at a final concentration of 25 μM asa substitute for 0.01 N NaOH. In a competitive binding test fordetermining the K_(i) value based on the K_(D) value thus determined,cells were incubated in 0.4 mL of an assay buffer containing 5 nM ofD-erythro-sphingosine-3-[³H]-1-phosphate and 0 to 1 μM of a testcompound for 60 minutes on ice. The subsequent procedures followingwashing were carried out as in the saturation binding test and theradioactivity was measured as described above.

Results:

The present invention compounds showed inhibitory activities of 50% orhigher on the binding of S1P to EDG-6 at 100 μmol/L. For example, theK_(i) value of 3-[3-(4-(5-phenylpentyloxy)phenyl)propylamino]propanoicacid was 0.352 μmol/L.

Biological Example 2 Measurement of Inhibitory Activity of the PresentInvention Compound on Binding of [³H]-PhS1P to EDG-6 Method:

A similar experiment was carried out by using cell membrane fraction ofan EDG-6-overexpressing CHO. Using 1 mg protein/mL of the membranefraction, reaction was carried out in a 96-well plate. Into each well,80 μL of a vehicle (DMSO) solution diluted with 2× binding buffer (100mmol/L Tris pH 7.5, 200 mM NaCl, 30 mM NaF, 1% BSA) or a ligand solutionhaving a twice higher concentration and 40 μL of 10 nmol/L [³H]-PhS1P(5,5,6,6,-tetralithium phytosphingosine 1 phosphate: This was preparedin the following manner. A compound (anti-7: tert-butyl(4S)-4-[(1S,2R)-1-(benzyloxy)-2-hydroxyhexadec-3-yn-1-yl]-2,2-dimethyl-1,3-oxazolizine-3-carboxylate)prepared in accordance with a method reported in a document (TetrahedronLett., 38(34), 6027-6030 (1997)) was reacted with benzyl bromide intetrahydrofuran in the presence of potassium hexamethyldisilylamide tothereby protect the hydroxy group. Then, it was treated in hydrogenchloride/methanol to removal of acetonide group. The compound thusobtained was reacted withN,N-diethyl-1,5-dihydro-2,4,3-benzodioxaphosphepin-3-amine indichloromethane in the presence of tetrazole and then oxidized withm-chloroperbenzoic acid. Then, it was reacted in the presence of ASCA-2catalyst (manufactured by NE Chemcat, 4.5% palladium-0.5% platinumcatalyst carried on active carbon, see, Fine Chemical, Oct. 1, 2002,pages 5 to 14) in methanol under a tritium atmosphere. The obtainedcompound was treated with a 4 N hydrogen chloride/1,4-dioxane solutionin dichloromethane to thereby give the desired compound) were added.Further, 40 μl of the membrane fraction solution was added and reactedat room temperature for 60 minutes. After the completion of thereaction, the reaction mixture was filtered by aspiration with a 96-wellUnifilter, washed with 50 mL of a washing buffer (50 mmol/L Tris pH7.5,0.5% BSA) thrice and dried at 60° C. for 45 minutes. Then, 50 μl/well ofMicro Scint 20 was added and the plate was covered with Top Seal-P.Next, the radioactivity was measured with Top Count (Perkin Elmer).

Results:

The present invention compounds showed inhibitory activities of 50% orhigher on the binding of S1P to EDG-6 at 100 μmol/L.

Biological Example 3 Evaluation of an Agonistic Activity Against EDG ofthe Present Invention Compound by Monitoring Changes in IntracellularCalcium Ion Concentration [Ca²⁺]_(i) Method:

Human EDG-1, EDG-3, EDG-5 or EDG-8 gene overexpressing Chinese HamsterOvary (CHO) cells were cultured in Ham's F12 medium (manufactured byGIBCO BRL) containing 10% FBS (fetal bovine serum),penicillin/streptomycin and blasticidin (5 μg/ml). The cultured cellswere incubated in a 5 μM Fura2-AM solution (Ham's F12 medium containing10% of FBS, 20 mM HEPES buffer (pH7.4) and 2.5 mM probenecid) at 37° C.for 60 minutes. After washing once with Hanks solution containing 20 mMHEPES buffer (pH7.4) and 2.5 mM probenecid, the plate was soaked in thesame solution until assay. Then, the plate was set on a fluorescent drugscreening system (FDSS 6000; Hamamatsu Photonics) and the intracellularcalcium ion concentration was measured without stimulation for 30seconds. A test compound (final concentration: 1 nM to 10 μM,dimethylsulfoxide (DMSO) solution) was added and S1P (finalconcentration: 100 nM) was added 5 minutes thereafter. Then, theincrease in the intracellular calcium ion concentration was measuredbefore and after the addition of S1P at intervals of 3 seconds(excitation wavelength: 340 nm and 380 nm, fluorescence wavelength: 500nm).

The agonistic activity of the present invention compound against eachEDG was determined by using the peak value due to S1P-stimulation in awell containing DMSO as a substitute for the test compound as a controlvalue (A), comparing the value before the addition of the test compoundwith the increased value (B) in the fluorescent ratio after theaddition, and calculating the increase ratio (%) in the intracellularcalcium ion concentration [Ca²⁺]_(i) as: increase ratio (%)=(B/A)×100.Increase ratios of the test compound at individual concentrations weredetermined and the EC₅₀ was calculated.

Results:

For example, the EC₅₀ of3-[3-(4-(5-phenylpentyloxy)phenyl)propylamino]propanoic acid for EDG-1was 0.255 μmol/L.

Biological Example 4 Counting the Number of Lymphocyte in Blood (1)Method:

Test compounds were orally administered to male Sprague-Dawley rats(Charles Riber Laboratories, Japan, Ltd., 6-week-old at using). Four to72 hours after the administration, the blood was collected from theaorta abdominalis under ether anesthesia. Using a portion of the thuscollected blood, the number of blood cells were counted and the numberof lymphocyte, neutrophil and platelet were counted. Each group had 4 or5 animals.

Results:

It was indicated that the present invention compounds lowered the numberof lymphocyte in blood, thereby showing a strong lymphocyte homingeffect. It was also found out that the effects of lymphopenia of thepresent invention compounds were sustained even 72 hours after theadministration. For example,3-[3-(4-(5-phenylpentyloxy)phenyl)propylamino]propanoic acidconcentration-dependently lowered the number of lymphocyte in blood at10, 30 and 100 mg/kg 4 hours after the administration.

It is found out that the present invention compounds have an agonisticactivity against EDG-1 and an ability to bind to EDG-6 and, moreover, aneffect of lymphopenia over a long period of time.

Biological Example 5 Counting the Number of Lymphocyte in Blood (2)Method:

Test compounds were orally administered to male BALB/c mice. Four to 72hours after the administration, the blood was collected from the aortaabdominalis under ether anesthesia. The number of the total leucocytecount, the lymphocyte count, the neutrophil count, the erythrocytecount, the platelet count in blood and the hematocrit value weremeasured with a multipurpose automatic blood cell counter (SF-3000,Sysmex). Evaluation was made by referring the average blood cell countin a vehicle-administered group (vehicle group) as to 100% andcalculating the percentage of vehicle from the average blood cell countof each test compound-administered group. Based on the test compounddoses and percentages of vehicle, a calibration curve is formed and thedose of the compound required for lowering the blood cell count to 50%was calculated as ED₅₀.

Biological Example 6 Counting the Number of Lymphocyte in Blood (3)Method:

Test compounds of the present invention or a vehicle were orallyadministered everyday to male Sprague-Dawley rats (Charles RiberLaboratories, Japan, Ltd., 6-week-old at using). Then, theadministration of the test compounds or the vehicle was ceased and therecovery speed of the lymphocyte count in blood was monitored with timelapse. For example, the rats were divided into 10 groups and a testcompound was administered for 10 days to 5 groups while the vehicle wasadministered for 10 days to the other 5 groups. After the administrationfor 10 days, the lymphocytes in blood were counted by using rats of oneof the vehicle groups and one of the test compound-administered groupson the days 1, 2, 3, 4 and 5 after cease. The whole blood was collectedfrom the aorta abdominalis under ether anesthesia. Using a portion ofthe thus collected blood, the number of the blood cells were counted andthe lymphocyte count, the neutrophil count and the platelet count weredetermined by using a multipurpose automatic blood cell counter(SF-3000, Sysmex). Each group had 4 or 5 animals.

Biological Example 7 Study on Effect of Invention Compound of PromotingLymphocyte Homing into Lymphatic Organ (1: Histological Stain of LymphNod) Method:

Lymph nods were taken out from the Sprague-Dawley rats (Charles RiberLaboratories, Japan, 6-week-old at using) used in Biological Example 4to which the test compounds or the vehicle had been administered.According to a method commonly used in the art, the tissues wereformalin-fixed and tissue pieces were prepared. By using the doublestaining method with hematoxylin and eosin, the conditions in the lymphtissues, i.e., the cortex, medulla, marginal sinus and lymphatic sinusparts, etc. were observed.

Biological Example 8 Study on Effect of Invention Compound of PromotingLymphocyte Homing into Lymphatic Organ (1: Count the Lymphocyte in LymphOrgan) Method:

To male BALB/c mice, test compounds were orally administered. Twentyhours thereafter, the mice were killed by exsanguination under etheranesthesia. Immediately thereafter, various lymph organs such as Peyer'spatch and thymus were taken out. Then, lymphocytes were obtainedtherefrom and subjected to the subsequent analysis. Namely, the cellswere stained with the use of anti-CD3 antibody, anti-CD4 antibody,anti-CD8, anti-B220 antibody, etc. and various positive cells weremeasured by using a flow cytometer.

Biological Example 9 Chemotaxis Assay Method:

The spleen or lymph nod was taken out from mice and lymphocytes wereobtained therefrom in accordance with a method commonly used in the art(J. Immunol., 171, 3500-3507 (2003)). The lymphocytes (for example,1×10⁷ cells/mL) thus obtained were put on the upper layer of achemotactic chamber, while S1P or various chemokines such as CCL-5 andCCL-21 were put on the lower layer. Test compounds (either alone orsimultaneously) are added to the lower layer or the upper layer and thusthe inhibitory or promoting effects on the lymphocyte migration wereobserved.

Biological Example 10 Phenotype Analysis of Blood Cells Method:

The whole blood was collected from rats to which test compounds or avehicle alone had been administered. Then, cells were stained with theuse of anti-CD3 antibody, anti-CD45RA antibody, anti-CD4 antibody,anti-CD8a antibody, anti-CD161a antibody and the like. Thus, the effectsof the test compounds on the phenotype of blood cells were observed. Forexample, cells were suspended in a Spitz type test tube and 7-AADviability dye, FITC-labeled anti-CD3 antibody, FITC-labeled anti-CD45RAantibody, FITC-labeled anti-CD8b antibody, PE-labeled anti-CD4 antibodyand FITC-labeled anti-CD161a antibody were added and mixed. Then, themixture was allowed to stand at room temperature in a dark place for 15minutes. Next, a hemolytic reagent IO Test 3 Lysing Solution was added,followed by stirring and then they were allowed to stand at roomtemperature in a dark place for 10 minutes. Next, the mixture wascentrifuged at 1300 rpm (320 g) for 5 minutes. The precipitate wassuspended in 1 mL of DPBS and 10,000 or more cells were measured with aflow cytometer EPICS XL (Beackman Coulter).

Biological Example 11 Internalization Analysis of EDG-1 Protein Method:

By using EDG-1-overexpressing CHO cells, the internalization of EDG-1protein due to the stimulation with test compounds was observed inaccordance with a method reported in FASEB, 18, 551-553 (2004).

Formulation Examples

Formulation Examples carried out in the present invention are shownbelow.

Formulation Example 1

3-[3-(4-(5-Phenylpentyloxy)phenyl)propylamino]propanoic acid (100 g),calcium carboxymethylcellulose (disintegrant, 20.0 g), magnesiumstearate (lubricant, 10.0 g) and microcrystalline cellulose (870 g) weremixed in a conventional manner, punched them out to give 10,000 tabletseach containing 10 mg of the active ingredient.

Formulation Example 2

3-[3-(4-(5-Phenylpentyloxy)phenyl)propylamino]propanoic acid (200 g),mannitol (2 kg) and distilled water (50 L) were mixed in a conventionalmanner. Then the solution was filtered through a dustproofing filter,and then 5 ml aliquots were charged into ampoules, which were autoclavedto give 10,000 ampoules each containing 20 mg of the active ingredient.

INDUSTRIAL APPLICABILITY

The present invention is applicable to drugs as will be described below.

The present invention compounds represented by formula (I), saltsthereof, solvates thereof or prodrugs thereof are compounds having anability to bind to an S1P receptor, in particular EDG-6 and exhibitprolonged pharmacological action. Therefore, they are useful aspreventives and/or remedies in mammals, in particular, humans forrejection in transplantation, rejection of a transplanted organ,transplantation versus host disease, autoimmune diseases (systemic lupuserythematosus, rheumatoid arthritis, myasthenia gravis and the like),allergic diseases (atopic dermatitis, asthma and the like),inflammation, infection, ulcer, lymphoma, malignant tumor, leukemia,diseases associated with lymphocyte infiltration into a tissue and thelike.

In addition to the ability to bind to EDG-6, some of the presentinvention compounds have an agonistic activity against EDG-1 and,therefore, show an immunosuppressant effect and prolongedpharmacological action. Due to these characteristics, they are moreuseful as preventives and/or remedies for rejection in transplantation,transplantation versus host disease, autoimmune diseases, allergicdiseases and the like.

1. A compound represented by formula (I):

wherein ring A represents a cyclic group; ring B represents a cyclicgroup which may further have a substituent(s); X represents a bond or aspacer having 1 to 8 atoms in its main chain in which one atom in thespacer may be taken together with a substituent on ring B to form a ringgroup which may have a substituent(s); Y represents a bond or a spacerhaving 1 to 10 atoms in its main chain in which one atom in the spacermay be taken together with a substituent on ring B to form a ring groupwhich may have a substituent(s); n represents 0 or 1, wherein when n is0, m is 1 and R¹ represents a hydrogen atom or a substituent, and when nis 1, m is 0 or an integer of 1 to 7 and R¹ represents a substituent inwhich when m is 2 or more, plural R¹s are the same or different, a saltthereof, a solvate thereof or a prodrug thereof.
 2. The compoundaccording to claim 1, which is a compound represented by formula (I):

wherein all symbols have the same meanings as in claim 1, and wherein acompound represented by formula (Ia) is excluded:

wherein R^(1a) represents C1-8 alkyl, C1-8 alkoxy, a halogen atom, nitroor trifluoromethyl; ring A^(a) represents a C5-7 monocyclic carbocyclicgroup or a 5- to 7-membered monocyclic heterocyclic group containing oneor two nitrogen atoms, one oxygen atom and/or one sulfur atom; E^(a)represents —CH₂—, —O—, —S— or —NR^(6a)—, in which R^(6a) represents ahydrogen atom or C1-8 alkyl; R^(2a) represents C1-8 alkyl, C1-8 alkoxy,a halogen atom, nitro or trifluoromethyl; R^(3a) represents a hydrogenatom or C1-8 alkyl; R^(4a) represents a hydrogen atom or C1-8 alkyl, orR^(2a) and R^(4a) may be taken together to form —CH₂CH₂— or —CH═CH—;G^(a) represents —CONR^(7a)—, —NR^(7a)CO—, —SO₂NR^(7a)—, —NR^(7a)SO₂—,—CH₂NR^(7a)— or —NR^(7a)CH₂—, in which R^(7a) represents a hydrogenatom, C1-8 alkyl, Cyc1 or C1-8 alkyl substituted with Cyc1, and Cyc1represents a C5-7 monocyclic carbocyclic group or a 5- to 7-memberedmonocyclic heterocyclic group containing one or two nitrogen atoms, oneoxygen atom and/or one sulfur atom; Q^(a) represents C1-4 alkylene or

wherein J¹, J², J³ and J⁴ each independently represents a carbon atom ora nitrogen atom in which the number of the nitrogen atom(s) is 2 orless; R^(5a) represents (1) C1-8 alkyl, (2) a halogen atom, (3) nitro,(4) cyano, (5) trifluoromethyl, (6) trifluoromethoxy, (7) phenyl, (8)tetrazolyl, (9) —OR^(9a), (10) —SR^(10a), (11) —COOR^(11a), (12)—NR^(12a)R^(13a), (13) —CONR^(14a)R^(15a), (14) —SO₂NR^(16a)R^(17a),(15) —NR^(18a)COR^(19a), (16) —NR^(20a)SO₂R^(21a), (17) —SO₂R^(22a), or(18) —OP(O)(OR^(23a))₂, in which R^(9a) to R^(18a), R^(20a) and R^(23a)each independently represents a hydrogen atom, C1-8 alkyl, Cyc2 or C1-8alkyl substituted with Cyc2, or R^(12a) and R^(13a), R^(14a) andR^(15a), or R^(16a) and R^(17a) may be taken together with a nitrogenatom to which they are bound, to form a 5- to 7-membered monocyclicheterocyclic group containing one or two nitrogen atoms, one oxygen atomand/or one sulfur atom, in which the heterocyclic group may besubstituted with C1-8 alkyl, hydroxy or amino; R^(19a) and R^(21a) eachindependently represents C1-8 alkyl, Cyc2 or C1-8 alkyl substituted withCyc2; R^(22a) represents hydroxy, C1-8 alkyl, Cyc2 or C1-8 alkylsubstituted with Cyc2; and Cyc2 represents a C5-7 monocyclic carbocyclicgroup or a 5- to 7-membered monocyclic heterocyclic group containing oneor two nitrogen atoms, one oxygen atom and/or one sulfur atom; prepresents 0 or an integer of 1 to 5; q represents an integer of 4 to 6;r represents 0 or an integer of 1 to 4; s represents 0 or an integer of1 to 4; and

represents a single bond or a double bond.
 3. The compound according toclaim 2, which is represented by formula (IA):

wherein Y¹ and Y² each independently represents a bond or a spacerhaving 1 to 9 atoms in its main chain in which the total atom number ofthe main chains of Y¹ and Y² is 9 or less; R⁷ represents a hydrogen atomor a substituent, or may be taken together with one atom in the spacerrepresented by Y¹ and/or Y² to form a nitrogen-containing heterocyclicgroup which may have a substituent(s); and other symbols have the samemeanings as described in claim
 1. 4. The compound according to claim 2,which is represented by formula (IB):

wherein ring B¹ represents a nitrogen-containing heterocyclic groupwhich may have a substituent(s) in which a nitrogen atom in the spacerrepresented by Y is taken together with a substituent on ring B and Y¹;and other symbols have the same meanings as described in any one ofclaims 1 and
 3. 5. The compound according to claim 2, wherein ring A isa benzene, indane, indene or naphthalene ring.
 6. The compound accordingto claim 2, wherein ring B is a C5-12 monocyclic or bicyclic carbocyclicgroup which may have a substituent(s).
 7. The compound according toclaim 6, wherein ring B is a benzene or naphthalene ring which may havea substituent(s).
 8. The compound according to claim 2, wherein ring Bis a 5- to 12-membered monocyclic or bicyclic heterocyclic group whichcontains 1 to 3 hetero atoms selected from an oxygen atom, a nitrogenatom and a sulfur atom and may be partially or fully saturated.
 9. Thecompound according to claim 2, wherein ring B is a dihydronaphthalene,indene, 6,7-dihydro-5H-benzo[7]annulene, pyridine, indole, chromene,benzofuran, benzothiophene, benzoxazole, dihydrobenzoxepine,tetrahydroisoquinoline, isoindoline or tetrahydrobenzazepine ring whichmay have a substituent(s).
 10. The compound according to claim 4,wherein the nitrogen-containing heterocyclic group represented by ringB¹ is a pyrrole, tetrahydropyridine, dihydropyrrole or tetrahydroazepinering.
 11. The compound according to claim 2, wherein X is a divalentgroup having 1 to 8 atoms in its main chain which is 1 to 4 combinationsselected from the group consisting of C1-8 alkylene which may besubstituted, C2-8 alkenylene which may be substituted, a nitrogen atomwhich may be substituted, —CO—, —O—, C3-6 cycloalkylene which may besubstituted and phenylene which may be substituted.
 12. The compoundaccording to claim 11, wherein X is —CH₂—, —(CH₂)₂—, —(CH₂)₃—, —(CH₂)₄—,—(CH₂)₅—, —(CH₂)₆—, —(CH₂)₇—, —(CH₂)₈—, —CH₂—O—, —(CH₂)₂—O—, —(CH₂)₃—O—,—(CH₂)₄—O—, —(CH₂)₅—O—, —CH═CH—CH₂—O— or -cyclopropylene-CH₂—O—, whicheach may be substituted, in which the right side of each group is boundto ring B.
 13. The compound according to claim 2, wherein Y is adivalent group having 1 to 10 atoms in its main chain which is 1 to 4combinations selected from the group consisting of C1-10 alkylene whichmay be substituted, C2-10 alkenylene which may be substituted, C2-10alkynylene which may be substituted, a nitrogen atom which may besubstituted, —CO—, —O—, —S—, phenylene which may be substituted,-(aziridine which may be substituted)-, -(azetidine which may besubstituted)-, -(pyrrolidine which may be substituted)-, -(piperidinewhich may be substituted)-, -(piperazine which may be substituted)- and-(tetrahydropyridine which may be substituted)-.
 14. The compoundaccording to claim 13, wherein Y is —(CH₂)₃—NHCH₂—, —(CH₂)₃—NCH₃—CH₂—,—(CH₂)₃—NH—(CH₂)₂—, —(CH₂)₂—NH—(CH₂)₂—, —(CH₂)₂—CONHCH₂—,—(CH₂)₂—CONH-(m-phenylene)-, —CR^(Y1)═CH—CH₂—NH—(CH₂)₄—,—CR^(Y1)═CH—CH₂—NH—(CH₂)₅—, —CR^(Y1)═CH—CH₂—NH—(CH₂)₂—,—CH═CR^(Y1)—CH₂—NH—(CH₂)₂—, —CR^(Y1)═CH—CH₂—NH—CH₂—, —CH₂-(azetidine)-,—(CH₂)₂-(azetidine)-, —(CH₂)₃-(azetidine)-,—CR^(Y1)═CH—CH₂-(azetidine)-, —CH═CR^(Y1)—CH₂-(azetidine)-,—(CH₂)₃-(piperidine)- or —CR^(Y1)═CH—CH₂-(piperidine)-, which each maybe substituted, in which R^(Y1) represents a hydrogen atom, a halogenatom or C1-4 alkyl which may be substituted with 1 to 3 halogen atoms,and the right side of each group is bound to ring B.
 15. The compoundaccording to claim 3, wherein Y¹ is a divalent group having 1 to 4 atomsin its main chain which is 1 to 4 combinations selected from the groupconsisting of C1-3 alkylene and —CO—.
 16. The compound according toclaim 15, wherein Y¹ is —CH₂—, —(CH₂)₂—, —(CH₂)₂—CO—, —CO—(CH₂)₂— or—(CH₂)₃—, which each may be substituted.
 17. The compound according toclaim 3, wherein Y² is a divalent group having 1 to 5 atoms in its mainchain which is 1 to 4 combinations selected from the group consisting ofC1-3 alkylene which may be substituted and phenylene which may besubstituted.
 18. The compound according to claim 17, wherein Y² is—CH₂—, —(CH₂)₂— or -(m-phenylene)-, which each may be substituted. 19.The compound according to claim 2, wherein the substituent representedby R¹ is a halogen atom, C1-20 alkyl which may be substituted, or C1-20alkyloxy which may be substituted.
 20. The compound according to claim19, wherein the substituent represented by R¹ is fluoro, chloro, bromo,methyl, trifluoromethyl or methoxy.
 21. The compound according to claim3, wherein R⁷ is a hydrogen atom or C1-20 alkyl which may besubstituted.
 22. The compound according to claim 2, which is a compoundrepresented by formula (I-S-3a):

wherein X^(S) has the same meaning as X described in claim 1, in whichX^(S) is not —(CH₂)_(q)-E^(a)-; R^(S0), R^(S1), R^(S2), R^(S3), R^(S4),R^(S5), R^(S6), R^(S7), R^(S8), R^(S9), R^(S10) and R^(S11) eachindependently represents a hydrogen atom, a halogen atom, or C1-4 alkylwhich may be substituted with 1 to 3 halogen atoms; E^(a), q and othersymbols have the same meanings as described in any one of claims 1 and2, or formula (I-S-7a):

wherein R^(S0), R^(S1), R^(S2), R^(S3), R^(S4), R^(S5) and R^(S6) eachhas the same meaning as described above; R^(S12), R^(S13), R^(S14) andR^(S15) each independently represents a hydrogen atom, a halogen atom,or C1-4 alkyl which may be substituted with 1 to 3 halogen atoms; E^(a),q and other symbols have the same meanings as described in any one ofclaims 1 and
 2. 23. The compound according to claim 2, which is acompound represented by formula (I-T):

wherein R^(S16), R^(S17), R^(S18), R^(S19) and R^(S20) eachindependently represents a hydrogen atom, a halogen atom, or C1-4 alkylwhich may be substituted with 1 to 3 halogen atoms; and other symbolshave the same meanings as described in any one of claims 1, 2 and 22.24. The compound according to claim 2, which is a compound representedby formula (I-U):

wherein R^(S21), R^(S22), R^(S23), R^(S24), R^(S25) and R^(S26) eachindependently represents a hydrogen atom, a halogen atom, or C1-4 alkylwhich may be substituted with 1 to 3 halogen atoms; and other symbolshave the same meanings as described in any one of claims 1, 2 and 22.25. The compound according to claim 2, which is (1)N-{(2E)-3-[4-(3-phenylpropoxy)phenyl]prop-2-enyl}-β-alanine, (2)N-{[6-(3-phenylpropoxy)-2-naphthyl]methyl}-β-alanine, (3)1-{[6-(3-phenylpropoxy)-2-naphthyl]methyl}azetidine-3-carboxylic acid,(4) 1-{[6-(3-phenylpropoxy)-2-naphthyl]methyl}piperidine-4-carboxylicacid, (5)N-{(2E)-3-[2-methyl-4-(3-phenylpropoxy)phenyl]prop-2-enyl}-β-alanine,(6)1-{(2E)-3-[4-(3-phenylpropoxy)phenyl]-2-propenyl}piperidine-4-carboxylicacid, (7)1-{(2E)-3-[4-(3-phenylpropoxy)phenyl]-2-propenyl}azetidine-3-carboxylicacid, (8) N-{3-[4-(3-phenylpropoxy)phenyl]propyl}-β-alanine, (9)3-({(2E)-3-[4-(3-phenylpropyl)phenyl]-2-butenyl}amino)propanoic acid,(10)3-({(2E)-3-[4-(3-cyclohexylpropoxy)-2-methylphenyl]-2-propenyl}amino)propanoicacid, (11)1-{[1-methyl-6-(4-phenylbutoxy)-3,4-dihydro-2-naphthalenyl]methyl}-3-azetidinecarboxylicacid, (12) N-{[1-(5-phenylpentyl)-1H-indol-5-yl]methyl}-β-alanine, (13)3-[4-[4-(3-phenylpropoxy)phenyl]-3,6-dihydropyridin-1(2H)-yl]propanoicacid, (14)1-(6-[3-(4-chlorophenyl)propoxy]-1-methyl-3,4-dihydro-2-naphthalenylmethyl)-3-azetidinecarboxylicacid, or (15)1-(6-[3-(4-fluorophenyl)propoxy]-1-methyl-3,4-dihydro-2-naphthalenylmethyl)-3-azetidinecarboxylicacid.
 26. The compound according to claim 1, which is (1)N-((2E)-3-{2-methyl-4-[(5-phenylpentyl)oxy]phenyl}prop-2-enyl)-3-alanine,(2) N-((2E)-3-{4-[(5-phenylpentyl)oxy]phenyl}-2-propenyl)-3-alanine, or(3)3-({[1-methyl-6-(4-phenylbutoxy)-3,4-dihydro-2-naphthalenyl]methyl}amino)propanoicacid.
 27. A pharmaceutical composition which comprises a compoundrepresented by formula (I) in claim 1, a salt thereof, a solvate thereofor a prodrug thereof.
 28. The pharmaceutical composition according toclaim 27, which is an S1P receptor binding agent.
 29. The pharmaceuticalcomposition according to claim 28, which is an EDG-6 binding agent whichmay have an ability to bind to EDG-1.
 30. The pharmaceutical compositionaccording to claim 29, wherein the EDG-6 binding agent which may have anability to bind to EDG-1 is an EDG-6 agonist which may have an agonisticactivity against EDG-1.
 31. The pharmaceutical composition according toclaim 27, which is an agent for preventing and/or treating a diseaserelated to EDG-1 and/or EDG-6.
 32. The pharmaceutical compositionaccording to claim 31, wherein the disease related to EDG-1 and/or EDG-6is rejection in transplantation, autoimmune disease and/or allergicdisease.
 33. The pharmaceutical composition according to claim 31,wherein the disease related to EDG-1 and/or EDG-6 is rejection intransplantation of kidney, liver, heart, lung, dermal graft, cornea,bone, bone marrow cells and/or pancreatic islet cells, collagen disease,systemic lupus erythematosus, rheumatoid arthritis, multiple sclerosis,psoriasis, inflammatory bowel disease, Crohn's disease, autoimmunediabetes, lung fibrosis, atopic dermatitis and/or asthma.
 34. Thepharmaceutical composition according to claim 27, which is animmunosuppressant agent.
 35. The pharmaceutical composition according toclaim 27, which is an agent causing lymphopenia.
 36. The pharmaceuticalcomposition according to claim 28, which comprises (1)2-[3-(4-(5-phenylpentyloxy)phenyl)propanoylamino]acetic acid, (2)3-[3-(4-(5-phenylpentyloxy)phenyl)propylamino]propanoic acid, (3)3-[2-(4-(5-phenylpentyloxy)phenyl)ethylamino]propanoic acid, (4)2-[3-(4-(5-phenylpentyloxy)phenyl)propylamino]acetic acid, (5)2-[N-methyl-3-(4-(5-phenylpentyloxy)phenyl)propylamino]acetic acid, (6)N-((2E)-3-{2-methyl-4-[(5-phenylpentyl)oxy]phenyl}prop-2-enyl)-(3-alanine,(7) N-((2E)-3-{4-[(5-phenylpentyl)oxy]phenyl}-2-propenyl)-β-alanine, (8)3-({[1-methyl-6-(4-phenylbutoxy)-3,4-dihydro-2-naphthalenyl]methyl}amino)propanoicacid, (9)3-carboxyl-5-[3-(4-(5-phenylpentyloxy)phenyl)propanoylamino]benzoicacid, or (10)2-chloro-5-[3-(2-fluoro-4-(5-phenylpentyloxy)phenyl)propanoylamino]benzoicacid, a salt thereof, a solvate thereof or a prodrug thereof.
 37. Amedicament comprising the compound represented by formula (I) accordingto claim 1, a salt thereof, a solvate thereof or a prodrug thereof incombination with one or at least two selected from the group consistingof an antimetabolite, an alkylating agent, a T cell activationinhibitor, a calcineurin inhibitor, a proliferation signal inhibitor, asteroid, an immunosuppressant agent, an antibody used in immunesuppression, an agent for treating rejection, an antibiotic, anantiviral agent and an antifungal agent.
 38. An immunosuppressant agentand/or an agent causing lymphopenia, which comprises a compound whichhas an ability to bind to EDG-6 and may have an ability to bind toEDG-1.
 39. The immunosuppressant agent and/or the agent causinglymphopenia according to claim 38, which is an agent for preventingand/or treating rejection in transplantation, autoimmune disease and/orallergic disease.
 40. A method for preventing and/or treating a diseaserelated to EDG-1 and/or EDG-6 in a mammal, which comprises administeringto a mammal an effective amount of the compound represented by formula(I) according to claim 1, a salt thereof, a solvate thereof or a prodrugthereof.
 41. A method for immune suppression and/or lymphopenia in amammal, which comprises administering to a mammal an effective amount ofthe compound represented by formula (I) according to claim 1, a saltthereof, a solvate thereof or a prodrug thereof.
 42. The pharmaceuticalcomposition according to claim 31, which comprises (1)2-[3-(4-(5-phenylpentyloxy)phenyl)propanoylamino]acetic acid, (2)3-[3-(4-(5-phenylpentyloxy)phenyl)propylamino]propanoic acid, (3)3-[2-(4-(5-phenylpentyloxy)phenyl)ethylamino]propanoic acid, (4)2-[3-(4-(5-phenylpentyloxy)phenyl)propylamino]acetic acid, (5)2-[N-methyl-3-(4-(5-phenylpentyloxy)phenyl)propylamino]acetic acid, (6)N-((2E)-3-{2-methyl-4-[(5-phenylpentyl)oxy]phenyl}prop-2-enyl)-β-alanine,(7) N-((2E)-3-{4-[(5-phenylpentyl)oxy]phenyl}-2-propenyl)-β-alanine, (8)3-({[1-methyl-6-(4-phenylbutoxy)-3,4-dihydro-2-naphthalenyl]methyl}amino)propanoicacid, (9)3-carboxyl-5-[3-(4-(5-phenylpentyloxy)phenyl)propanoylamino]benzoicacid, or (10)2-chloro-5-[3-(2-fluoro-4-(5-phenylpentyloxy)phenyl)propanoylamino]benzoicacid, a salt thereof, a solvate thereof or a prodrug thereof.
 43. Thepharmaceutical composition according to claim 34, which comprises (1)2-[3-(4-(5-phenylpentyloxy)phenyl)propanoylamino]acetic acid, (2)3-[3-(4-(5-phenylpentyloxy)phenyl)propylamino]propanoic acid, (3)3-[2-(4-(5-phenylpentyloxy)phenyl)ethylamino]propanoic acid, (4)2-[3-(4-(5-phenylpentyloxy)phenyl)propylamino]acetic acid, (5)2-[N-methyl-3-(4-(5-phenylpentyloxy)phenyl)propylamino]acetic acid, (6)N-((2E)-3-{2-methyl-4-[(5-phenylpentyl)oxy]phenyl}prop-2-enyl)-β-alanine,(7) N-((2E)-3-{4-[(5-phenylpentyl)oxy]phenyl}-2-propenyl)-β-alanine, (8)3-({[1-methyl-6-(4-phenylbutoxy)-3,4-dihydro-2-naphthalenyl]methyl}amino)propanoicacid, (9)3-carboxyl-5-[3-(4-(5-phenylpentyloxy)phenyl)propanoylamino]benzoicacid, or (10)2-chloro-5-[3-(2-fluoro-4-(5-phenylpentyloxy)phenyl)propanoylamino]benzoicacid, a salt thereof, a solvate thereof or a prodrug thereof.
 44. Thepharmaceutical composition according to claim 35, which comprises (1)2-[3-(4-(5-phenylpentyloxy)phenyl)propanoylamino]acetic acid, (2)3-[3-(4-(5-phenylpentyloxy)phenyl)propylamino]propanoic acid, (3)3-[2-(4-(5-phenylpentyloxy)phenyl)ethylamino]propanoic acid, (4)2-[3-(4-(5-phenylpentyloxy)phenyl)propylamino]acetic acid, (5)2-[N-methyl-3-(4-(5-phenylpentyloxy)phenyl)propylamino]acetic acid, (6)N-((2E)-3-{2-methyl-4-[(5-phenylpentyl)oxy]phenyl}prop-2-enyl)-β-alanine,(7) N-((2E)-3-{4-[(5-phenylpentyl)oxy]phenyl}-2-propenyl)-β-alanine, (8)3-({[1-methyl-6-(4-phenylbutoxy)-3,4-dihydro-2-naphthalenyl]methyl}amino)propanoicacid, (9)3-carboxyl-5-[3-(4-(5-phenylpentyloxy)phenyl)propanoylamino]benzoicacid, or (10)2-chloro-5-[3-(2-fluoro-4-(5-phenylpentyloxy)phenyl)propanoylamino]benzoicacid, a salt thereof, a solvate thereof or a prodrug thereof.